Royalcanin GHA

Breeds Tested

1. 250+ Breeds, Types and Varieties

Affenpinscher
Afghan Hound
Airedale Terrier
Akita
Alaskan Klee Kai
Alaskan Malamute
American Bulldog
American English Coonhound
American Eskimo Dog
American Foxhound
American Hairless Terrier
American Staffordshire Terrier
American Water Spaniel
Anatolian Shepherd Dog
Argentine Dogo
Australian Cattle Dog
Australian Kelpie
Australian Koolie
Australian Shepherd
Australian Terrier
Barbet
Basenji
Basset Hound
Beagle
Bearded Collie
Beauceron
Bedlington Terrier
Belgian Malinois
Belgian Sheepdog
Belgian Tervuren
Bergamasco
Berger Picard
Bernese Mountain Dog
Bichon Frise
Biewer Terrier
Black and Tan Coonhound
Black Russian Terrier
Bloodhound
Bluetick Coonhound
Boerboel
Bolognese
Border Collie
Border Terrier
Borzoi
Boston Terrier
Bouvier des Flandres
Boxer
Boykin Spaniel
Briard
Brittany
Brussels Griffon
Bull Terrier
Bulldog
Bullmastiff
Cairn Terrier
Canaan Dog
Canadian Eskimo Dog
Cane Corso
Cardigan Welsh Corgi
Catahoula Leopard Dog
Cavalier King Charles Spaniel
Cesky Terrier
Chesapeake Bay Retriever
Chihuahua
Chinese Crested
Chinese Shar-Pei
Chinook
Chow Chow
Cirneco dell'Etna
Clumber Spaniel
Cocker Spaniel - American
Collie
Coton de Tulear
Curly-Coated Retriever
Dachshund - Miniature & Standard
Dalmatian
Dandie Dinmont Terrier
Doberman Pinscher
Dogue de Bordeaux
Dutch Shepherd Dog
English Cocker Spaniel
English Foxhound
English Setter
English Springer Spaniel
English Toy Spaniel
Entlebucher Mountain Dog
Field Spaniel
Finnish Lapphund
Finnish Spitz
Flat-Coated Retriever
French Bulldog
German Pinscher
German Shepherd Dog
German Shorthaired Pointer
German Spitz
German Wirehaired Pointer
Giant Schnauzer
Glen of Imaal Terrier
Golden Retriever
Gordon Setter
Grand Basset Griffon Vendéen
Great Dane
Great Pyrenees
Greater Swiss Mountain Dog
Greyhound
Harrier
Havanese
Ibizan Hound
Icelandic Sheepdog
Irish Red and White Setter
Irish Setter
Irish Terrier
Irish Water Spaniel
Irish Wolfhound
Italian Greyhound
Japanese Chin
Japanese Spitz
Jindo
Keeshond
Kerry Blue Terrier
Komondor
Kuvasz
Labrador Retriever
Lagotto Romagnolo
Lakeland Terrier
Lancashire Heeler
Large Münsterlander
Leonberger
Lhasa Apso
Löwchen
Maltese
Manchester Terrier - Toy & Standard
Maremma Sheepdog
Mastiff
McNab
Mi-ki
Miniature American Shepherd
Miniature Bull Terrier
Miniature Pinscher
Miniature Schnauzer
Mudi
Neapolitan Mastiff
Newfoundland
Norfolk Terrier
Norwegian Buhund
Norwegian Elkhound
Norwegian Lundehund
Norwich Terrier
Nova Scotia Duck Tolling Retriever
Old English Sheepdog
Otterhound
Papillon
Parson Russell Terrier
Pekingese
Pembroke Welsh Corgi
Petit Basset Griffon Vendéen
Pharaoh Hound
Plott Hound
Pointer
Polish Lowland Sheepdog
Pomeranian
Poodle - Toy, Miniature & Standard
Portuguese Podengo Pequeno
Portuguese Water Dog
Presa Canario
Pug
Puli
Pumi
Pyrenean Shepherd
Rat Terrier
Redbone Coonhound
Rhodesian Ridgeback
Rottweiler
Russell Terrier
Saint Bernard
Saluki
Samoyed
Schipperke
Scottish Deerhound
Scottish Terrier
Sealyham Terrier
Shetland Sheepdog
Shiba Inu
Shih Tzu
Siberian Husky
Silky Terrier
Skye Terrier
Sloughi
Small Münsterlander
Smooth Fox Terrier
Soft Coated Wheaten Terrier
Spanish Water Dog
Spinone Italiano
Staffordshire Bull Terrier
Standard Schnauzer
Sussex Spaniel
Swedish Vallhund
Tibetan Mastiff
Tibetan Spaniel
Tibetan Terrier
Toy Fox Terrier
Treeing Walker Coonhound
Vizsla
Weimaraner
Welsh Springer Spaniel
Welsh Terrier
West Highland White Terrier
Whippet
White Swiss Shepherd
Wire Fox Terrier
Wirehaired Pointing Griffon
Wirehaired Vizsla
Xoloitzcuintli
Yorkshire Terrier

Genetic Mutation Tests

1. Multi-drug Resistance 1 (MDR1)

MDR1 or Multi-Drug Resistance 1 is a genetic mutation found in many of the herding breeds, some sighthound breeds, and many mixed breed dogs. The MDR1 gene is responsible for production of a protein called P-glycoprotein. The P-glycoprotein molecule is a drug transport pump that plays an important role in limiting drug absorption and distribution (particularly to the brain) and enhancing the excretion/elimination of many drugs used in dogs.

Some dogs, particularly herding breeds or mixed-breed dogs with herding breed ancestry have a mutation in the MDR1 gene that makes them defective in their ability to limit the absorption and distribution of many drugs. These dogs are also slower to eliminate drugs from the body that are transported by P-glycoprotein. As a result, dogs with the MDR1-mutation may have severe adverse reactions to some common drugs.

What about Mixed-breeds?
Our tests look for the presence of purebreds in your dog’s heritage back to the great-grandparent level. Just because we don’t find a pedigree herding breed in your dog’s last three generations, doesn’t mean he or she doesn’t have one further back in their ancestry. Therefore, even mixed breed dogs should be tested for the MDR1 mutation.

Origins of the Test
The discovery of the mutation of the multi-drug resistant gene (MDR1) and its effects on multidrug sensitivity in dogs was made by Washington State University. It is a patent-protected diagnostic test offered by Washington State University that has been licensed to Mars Veterinary for use in the ROYAL CANIN® Canine Genetic Analysis™ tests.

For more information about MDR1:
Contact Mars Veterinary at 1-888-597-3883 or customercare@marsveterinary.com , or visit the Washington State University School of Veterinary Medicine web site at: http://vcpl.vetmed.wsu.edu/.

Drugs affected by the MDR1 mutation:
Acepromazine
Butorphanol
Doxorubicin
Doramectin
Emodepside
Erythromycin
Ivermectin
Loperamide
Milbemycin
Moxidectin
Paclitaxel
Rifampin
Selamectin
Vinblastine
Vincristine

Breeds affected by the MDR1 Mutation (frequency %):
Australian Shepherd 50%
Australian Shepherd, Mini 50%
Border Collie < 5%
Collie 70 %
English Shepherd 15 %
German Shepherd 10 %
Herding Breed Cross 10 %
Long-haired Whippet 65 %
McNab 30 %
Mixed Breed 5 %
Old English Sheepdog 5 %
Shetland Sheepdog 15 %
Silken Windhound 30 %

Disease Tests

1. Acral Mutilation Syndrome, (AMS)

Disease Category Type
neurologic

Description
Acral mutilation syndrome is a severe hereditary sensory neuropathy. The disorder is characterized by loss of pain sensation in the paws that causes paw ulceration and self-mutilation. This disorder affects only the sensory neurons and is caused by their abnormal development and progressive degeneration. The inheritance pattern for this disorder is autosomal recessive.

Clinical Overview
Clinical signs of the disease typically emerge at around four months of age. The paws of affected dogs are insensitive to pain. Affected dogs tend to lick or bite their paws excessively. This self-mutilation is severe and often results in claw loss, fractures, and digit amputation. The motor abilities and proprioception of affected dogs remain normal. It has been suspected that the trigger for paw biting and licking in these dogs are minor paw injuries caused by insensitivity to pain. The disorder is severe and severely affected dogs require euthanasia.

Mutation Found In:
English Cocker Spaniel, Pointer, English Springer Spaniel, French Spaniel, German Shorthaired Pointer, Old English Sheepdog

Gene Variant Tested
AMS

Clinical Signs
loss of pain sensation in paws, self-mutilation of paws

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Plassais J, Lagoutte L, Correard S, Paradis M, Guaguère E, He ´dan B, Pommier A, Botherel N, Cadiergues MC, Pilorge P, Silversides D, Bizot M, Samuels M, Arnan C, Johnson R, Hitte C, Salbert G, Me ´reau A, Quignon P, Derrien T, Andre C. A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies. PLOS Genetics | DOI:10.1371/journal.pgen.1006482 December 29, 2016.

2. Acute Respiratory Distress Syndrome, (ARDS)

Disease Category Type
Other

Description
Acute respiratory distress syndrome is a rare, life-threatening disorder that causes acute, severe respiratory failure that is unresponsive to treatment. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Clinical signs of this disease emerge very acutely in dogs under one year of age. Early signs of the disease include noisy respiration, increased respiratory rate, vomiting, and weight loss. The disorder is unresponsive to treatment and quickly develops into severe respiratory distress that can be accompanied with other severe conditions, such as pneumomediastinum, hiatal herniation, or gastroesophageal intussusception. The disorder is unresponsive to treatment and affected dogs die or are euthanized between 1-6 weeks after the onset of respiratory signs.

Some affected dogs have been reported to exhibit other developmental anomalies such as hydrocephalus or renal aplasia. These anomalies are not directly linked to the respiratory signs and affected dogs usually grow and develop normally until the onset of respiratory signs.

Mutation Found In:
Dalmatian

Gene Variant Tested
ANLN

Clinical Signs
acute respiratory distress

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Holopainen S, Hytönen M, Syrjä P, Arumilli M, Järvinen A, Rajamäki M, Lohi H. ANLN truncation causes a familial fatal acute respiratory distress syndrome in Dalmatian dogs. PLoS Genet. 2017 Feb 21;13(2):e1006625. doi: 10.1371/journal.pgen.1006625. eCollection 2017.

3. Alaskan Husky Encephalopathy, (AHE)

Disease Category Type
neurologic

Description
Alaskan Husky encephalopathy (AHE) is a severe, early-onset disorder of the central nervous system encountered in Alaskan Huskies. The disorder often affects multiple dogs from the same litter. The underlying cause is a mutation in the gene encoding a transporter protein required for thiamine transport into the cells of the central nervous system. The disorder is inherited in an autosomal recessive manner and affected dogs are usually euthanized within 2-7 months from the onset of clinical signs.

Clinical Overview
The first signs of AHE are usually observed at the age of 6 months to 3 years of age. Affected dogs may have a sudden onset of clinical signs or a chronic history with slowly progressing signs. The characteristic signs of AHE include generalized seizures, altered mentation, behavioral changes, dysphagia (eating difficulties), loss of vision, hypermetria (overreaching movements), ataxia (uncoordinated movements), and tetraparesis (weakness in voluntary movement of all four limbs). Affected dogs are usually euthanized within 2-7 months from the onset of clinical signs although some dogs may live for months to years before the signs progress.

Mutation Found In:
Alaskan Husky

Gene Variant Tested
SLC19A3

Clinical Signs
seizures, altered mentation, behavioral abnormalities, dysphagia, central blindness, hypermetria, ataxia, and tetraparesis

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Vernau KM, Runstadler JA, Brown EA, Cameron JM, Huson HJ, Higgins RJ, Ackerley C, Sturges BK, Dickinson PJ, Puschner B, Giulivi C, Shelton GD, Robinson BH, DiMauro S, Bollen AW, Bannasch DL. Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan Husky encephalopathy. PLoS One 8:e57195, 2013.

Brenner O, Wakshlag JJ, Summers BA, de Lahunta A. Alaskan Husky encephalopathy - a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome). Acta Neuropathol 2000;100:50-62.

4. Alexander Disease, (AxD); mutation originally found in Labrador Retriever

Disease Category Type
neurologic

Description
Alexander disease is a rare, fatal hereditary neurological disease. The disorder causes progressively worsening weakness of voluntary movement in all limbs. The disorder is caused by the dysfunction of astrocyte cells in the central nervous system and is inherited in an autosomal recessive manner.

Clinical Overview
Clinical signs of this disorder emerge around three months of age and begin with weakness of movement in the limbs, causing a spastic swimming-puppy-like position of the front limbs. The dog can also develop other neurological signs, such as mild vestibular signs and myoclonic jerks. The chest of affected puppies can be flat and regurgitation can occur. The disorder is progressive and in a few weeks, the weakness of voluntary movement of the limbs progresses to where the dog is unable to stand.

Mutation Found In:
Labrador Retriever

Gene Variant Tested
GFAP:c.716G>A

Clinical Signs
progressive tetraparesis, regurgitation, myoclonic jerks

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Van Poucke M, Martlé V, Van Brantegem L, Ducatelle R, Van Ham L, Bhatti S, Peelman LJ. A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever. Eur J Hum Genet. 2016 Jun;24(6):852-6. doi: 10.1038/ejhg.2015.223. Epub 2015 Oct 21.

5. Amelogenesis Imperfecta, (AI)

Disease Category Type
dental

Description
Amelogenesis imperfecta (AI) or enamel hypoplasia is a congenital disorder characterized by defects in enamel formation. Enamel is a hard, smooth substance that covers the crown of the tooth providing protection to the underlying dentine. Normal enamel functions to strengthen the teeth, seal the teeth from bacteria, and prevent plaque from accumulating on the surface of the teeth. The clinical signs of amelogenesis imperfecta include enamel thinning and roughening and discoloration of the teeth. Amelogenesis imperfecta is known to affect both the Italian Greyhound and the Standard Poodle, but the genetic cause for the disease has only been identified in the Italian Greyhound. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Amelogenesis imperfecta is characterized by defects in the enamel formation of both baby teeth and permanent teeth. Enamel formation starts before the eruption of the first teeth and there will be no subsequent repair of the enamel after eruption. The enamel of affected teeth erodes more rapidly over the years than normal enamel. The teeth of affected dogs are pitted, rough, and discolored brown. Affected teeth are often small and pointed with increased gaps. Amelogenesis imperfecta is relatively mild in Italian Greyhounds and the affected teeth function in a nearly normal fashion. There is no treatment available for amelogenesis imperfecta, but most dogs live a normal life with mild signs.

Mutation Found In:
Italian Greyhound

Gene Variant Tested
ENAM

Clinical Signs
discolored teeth, enamel roughening, enamel thinning, and small, pointed teeth

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gandolfi B, Liu H, Griffioen L, Pedersen NC. Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds. Anim Genet 44:569-78, 2013.

6. Autosomal Recessive Congenital Ichthyosis, (ARCI); mutation originally found in American Bulldog

Disease Category Type
dermal

Description
Ichthyoses are hereditary disorders affecting skin cornification. There are many different forms of ichthyoses and the genetic background and severity of the clinical signs vary between different dog breeds. The ichthyosiform disorder in American Bulldogs is visible before weaning and persists through life. The disorder is most probably linked to abnormal lipid metabolism in the epidermis. The mode of inheritance is autosomal recessive.

Clinical Overview
Clinical signs of this disorder can be seen in puppies even before they are weaned. The coat of affected puppies is scruffy and the glabrous skin is reddish and has light brown scale on it, giving it a wrinkly appearance. The disorder persists through life and adult dogs have a reddish-brown discoloration across their abdomen, axillae, and inguinal regions and scaling is present throughout the body. Problems associated with this disorder include possibly severe Malassezia (yeast) overgrowth causing ear and skin infections.

Mutation Found In:
American Bulldog

Gene Variant Tested
NIPAL4

Clinical Signs
reddish-brown skin, scaling skin, secondary skin infections

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Casal M, Wang P, Mauldin E, Lin G, Henthorn P. A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs. PLoS One. 2017 Jan 25;12(1):e0170708. doi: 10.1371/journal.pone.0170708. eCollection 2017.

Mauldin E. Canine ichthyosis and related disorders of cornification in small animals. Vet Clin North Am Small Anim Pract. 2013 Jan; 43(1): 89–97.doi: 10.1016/j.cvsm.2012.09.005 PMCID: PMC3529142 NIHMSID: NIHMS421805

7. Autosomal Recessive Severe Combined Immunodeficiency, (ARSCID)

Disease Category Type
immunologic

Description
Autosomal recessive severe combined immunodeficiency (ARSCID) is a severe autosomal recessive immunodeficiency disorder discovered in Jack Russell Terriers. Affected dogs are highly susceptible to recurrent infections and usually die at a young age.

Clinical Overview
ARSCID causes severe immunodeficiency because of the low number of lymphocytic white blood cells involved in immune defense. There is a complete absence of IgM antibodies in serum. Affected dogs show incomplete development of the lymphoid tissue and are highly susceptible to recurrent infections and usually die at a young age secondary to infection, once maternal antibodies wane. Necropsy results show hypoplasia of all lymphoid tissues.

Mutation Found In:
Jack Russell Terrier, Parson Russell Terrier

Gene Variant Tested
PRKDC

Clinical Signs
immunodeficiency, lymphopenia, and lymphoid hypoplasia

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Bell TG, Butler KL, Sill HB, Stickle JE, Ramos-Vara JA, Dark MJ. Autosomal recessive severe combined immunodeficiency of Jack Russell Terriers. J Vet Diagn Invest 14:194-204, 2002.

Ding, Q., Bramble, L., Yuzbasiyan-Gurkan, V., Bell, T., Meek, K. DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia. Gene 283:263-269, 2002.

Meek K, Kienker L, Dallas C, Wang W, Dark MJ, Venta PJ, Huie ML, Hirschhorn R, Bell T. SCID in Jack Russell terriers: a new animal model of DNA-PKcs deficiency. J Immunol 167:2142-50, 2001

8. Bandera's Neonatal Ataxia, (BNAt)

Disease Category Type
neurologic

Description
Inherited ataxias (i.e. cerebellar ataxias) are a heterogenic group of disorders. The onset of disease and progression depend on the type of ataxia in question. Clinical signs may occur in young puppies, juveniles, or in dogs a few years of age. Neonatal (i.e. newborn) cerebellar ataxia is an early onset, severe neurological disease. Affected puppies show signs such as difficulties in movement starting at 2 weeks of age. This disease was identified in the Coton de Tulear breed. There is another type of cerebellar ataxia found in the Coton de Tulear breed, but it is associated with a later onset. The mode of inheritance of neonatal cerebellar ataxia is autosomal recessive.

Clinical Overview
First signs are observed as soon as the puppies start to move around 2 weeks of age. Usually, affected puppies are unable to stand or walk on their own and they appear to move as if they were swimming. In addition, they often roll-over on their side, at which point opisthotonus (head and cervical spine arched upwards) and paddling of the legs is observed. Other signs are nodding of the head, intention tremors, and jerky movements of the eyes. Clinical signs do not usually progress, but due to their severity affected puppies are usually euthanized.

Mutation Found In:
Coton de Tulear

Gene Variant Tested
GRM1

Clinical Signs
locomotory problems, head titubation, and intention tremors

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Zeng R, Farias FHG, Johnson GS, McKay SD, Schnabel RD, Decker JE, Taylor JF, Mann CS, Katz ML, Johnson GC, Coates JR, O'Brien DP. A Truncated Retrotransposon Disrupts the GRM1 Coding Sequence in Coton de Tulear Dogs with Bandera's Neonatal Ataxia. J Vet Intern Med 25:267-272, 2011.

Coates JR, O'Brien DP, Kline KL, Storts RW, Johnson GC, Shelton GD, Patterson EE, Abbott LC. Neonatal cerebellar ataxia in Coton de Tulear dogs. J Vet Intern Med 2002;16:680-689.

9. Benign Familial Juvenile Epilepsy or Remitting Focal Epilepsy

Disease Category Type
neurologic

Description
Benign familial juvenile epilepsy (BFJE) is a neurological disorder encountered in the Lagotto Romagnolo breed. Affected dogs suffer from focal-onset epileptic seizures in puppyhood. The seizures invariably resolve spontaneously by four months of age. In some cases, carriers might also present epileptic signs. BFJE is inherited in an autosomal recessive manner.

Clinical Overview
Epileptic seizures are caused by a disruption of the normal electrochemical activity of the brain. Onset of focal epileptic seizures in BFJE is at 5-9 weeks of age. The seizures consist of whole-body tremors, ataxia (uncoordinated movements), and stiffness. The epileptic signs can sometimes be associated with alterations of consciousness. Frequency of seizures can vary between individuals: there can be several seizures a day or sporadic seizures a few times a week. Usually an affected puppy seems completely normal between the seizures. However, in severe cases there can be neurological signs, such as generalized ataxia between the seizures. BFJE form of epilepsy is relatively benign since the seizures typically end after 4 months of age.

Mutation Found In:
Lagotto Romagnolo

Gene Variant Tested
LGI2

Clinical Signs
focal-onset epileptic seizures

Mode of Inheritance
recessive but may also affect some heterozygotes

Signs Seen in Affected Carriers
epileptic seizures

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Seppälä EH, Jokinen TS, Fukata M, Fukata Y, Webster MT, Karlsson EK, Kilpinen SK, Steffen F, Dietschi E, Leeb T, Eklund R, Zhao X, Rilstone JJ, Lindblad-Toh K, Minassian BA, Lohi H. LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs. PLoS Genet 7(7): e1002194, 2011.

Jokinen TS, Metsähonkala L, Bergamasco L, Viitmaa R, Syrjä P, Lohi H, Snellman M, Jeserevics J, Cizinauskas S. Benign Familial Juvenile Epilepsy in Lagotto Romagnolo Dogs. J Vet Intern Med 2007;21:464-471.

10. Bleeding disorder due to P2RY12 defect

Disease Category Type
blood

Description
This bleeding disorder, due to a defect in the P2RY12 receptor protein, was described in Greater Swiss Mountain Dogs. Affected dogs suffer from excessive and prolonged bleeding after a trauma or a surgery. The mode of inheritance of the disorder is autosomal recessive.

Clinical Overview
The bleeding disorder due to P2RY12 defect is a blood coagulation deficiency identified in Greater Swiss Mountain Dogs. The deficiency may lead to excessive bleeding in the event of surgery or trauma. The excessive bleeding is caused by a failure of blood platelet aggregation, and may potentially be fatal. Spontaneous bleeding is usually not encountered in affected dogs.

Mutation Found In:
Greater Swiss Mountain Dog

Gene Variant Tested
P2RY12

Clinical Signs
severe excessive bleeding after a trauma or a surgery and excessive or prolonged bleeding after a minor cut

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Boudreaux MK, Martin M P2Y12 receptor gene mutation associated with postoperative hemorrhage in a Greater Swiss Mountain dog. Vet Clin Pathol. 40(2):202-206, 2011.

11. Canine Leukocyte Adhesion Deficiency (CLAD) Type III

Disease Category Type
immunologic

Description
Canine leukocyte adhesion deficiency (CLAD) type III is a rare immunological disorder encountered in German Shepherd dogs. CLAD type III is characterized by immunodeficiency predisposing affected dogs to recurrent severe infections. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
CLAD III results from leukocytes being unable to migrate to the site of inflammation and participate in the phagocytosis of pathogens due to impaired activation of beta integrins. Persistent leukocytosis (increased number of leukocytes in the blood) and platelet dysfunction are characteristic for the disorder. The onset of symptoms is at the age of 6 months. Clinical signs include fever (pyrexia), increased mucosal hemorrhages, marked periodontal disease, poor wound healing, and lameness.

Mutation Found In:
German Shepherd Dog

Gene Variant Tested
FERMT3

Clinical Signs
persistent leukocytosis, pyrexia, marked periodontal disease, lameness, increased mucosal hemorrhages, impaired wound healing

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Hugo TB, Heading KL. Leucocyte adhesion deficiency III in a mixed-breed dog. Aust Vet J 92:299-302, 2014.

Boudreaux MK, Wardrop KJ, Kiklevich V, Felsburg P, Snekvik K. A mutation in the canine Kindlin-3 gene associated with increased bleeding risk and susceptibility to infections. Thromb Haemost 103:475-7, 2010.

12. Canine Multifocal Retinopathy 1, (CMR1); mutation found in Mastiff-related breeds

Disease Category Type
ocular

Description
Canine multifocal retinopathy 1 (CMR1) is an inherited disease found in multiple breeds. It is characterized by several localized, round, bullous alterations of variable size and location in the retina that cause retinal decay. CMR1 is an autosomal recessive disorder.

Clinical Overview
Typically, the first ocular fundus changes in CMR1 can be diagnosed by the age of four months. In many cases, the lesions may appear to heal or even go away, sometimes leaving no evidence or only a wrinkle at the site of the healed lesion. In almost all cases, lesions from CMR1 do not progress significantly over time, so there is generally no reduction in eyesight though more serious cases could exhibit vision impairment. Very seldom is the patient completely blinded.

Mutation Found In:
American Bulldog, American Pit Bull Terrier, Australian Shepherd, Boerboel, Bulldog, Bullmastiff, Cane Corso, Dogue de Bordeaux, French Bulldog, Great Pyrenees, Mastiff, Miniature American Shepherd, Presa Canario

Gene Variant Tested
BEST1

Clinical Signs
retinal degeneration

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Guziewicz KE, Slavik J, Lindauer SJ, Aguirre GD, Zangerl B. Molecular Consequences of BEST1 Gene Mutations in Canine Multifocal Retinopathy Predict Functional Implications for Human Bestrophinopathies. Invest Ophthalmol Vis Sci 52:4497-505, 2011.

Guziewicz KE, Zangerl B, Lindauer SJ, Mullins RF, Sandmeyer LS, Grahn BH, Stone EM, Acland GM, Aguirre GD. Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. Invest Ophthalmol Vis Sci 48:1959-67, 2007.

13. Canine Multifocal Retinopathy 2, (CMR2); mutation originally found in Coton de Tulear

Disease Category Type
ocular

Description
Canine multifocal retinopathy (CMR) is an inherited disease found in multiple breeds, with CMR2 noted in the Coton de Tulear. It is characterized by several localized, round, bullous alterations of variable size and location in the retina that cause retinal decay. CMR2 is an autosomal recessive disorder.

Clinical Overview
Typically, the first ocular fundus changes in CMR2 can be diagnosed by the age of four months. In many cases, the lesions may appear to heal or even go away, sometimes leaving no evidence or only a wrinkle at the site of the healed lesion. In almost all cases, lesions from CMR2 do not progress significantly over time, so there is generally no reduction in eyesight though more serious cases could exhibit vision impairment. Very seldom is the patient completely blinded. The lesions noted in CMR2 in Coton de Tulears tend to be more severe and persist longer than the lesions noted in breeds affected by the other CMR.

Mutation Found In:
Coton de Tulear

Gene Variant Tested
BEST1 G482A

Clinical Signs
retinal degeneration

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Guziewicz KE, Slavik J, Lindauer SJ, Aguirre GD, Zangerl B. Molecular Consequences of BEST1 Gene Mutations in Canine Multifocal Retinopathy Predict Functional Implications for Human Bestrophinopathies. Invest Ophthalmol Vis Sci 52:4497-505, 2011.

Guziewicz KE, Zangerl B, Lindauer SJ, Mullins RF, Sandmeyer LS, Grahn BH, Stone EM, Acland GM, Aguirre GD. Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. Invest Ophthalmol Vis Sci 48:1959-67, 2007.

14. Canine Multifocal Retinopathy 3, (CMR3); mutation originally found in Lapponian Herder

Disease Category Type
ocular

Description
Canine multifocal retinopathy (CMR) is an inherited disease found in multiple breeds. It is characterized by several localized, round, bullous alterations of variable size and location in the retina that cause retinal decay. CMR3 is a form of multifocal retinopathy observed in the Lapponian Herder. CMR3 is autosomal recessive disorder.

Clinical Overview
Typically, the first ocular fundus changes in CMR3 can be diagnosed by the age of four months. In many cases, the lesions may appear to heal or even go away, sometimes leaving no evidence or only a wrinkle at the site of the healed lesion. In almost all cases, lesions from CMR3 do not progress significantly over time, so there is generally no reduction in eyesight though more serious cases could exhibit vision impairment. Very seldom is the patient completely blinded.

Mutation Found In:
Lapponian Herder

Gene Variant Tested
BEST1 C1388del

Clinical Signs
retinal degeneration

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Guziewicz KE, Slavik J, Lindauer SJ, Aguirre GD, Zangerl B. Molecular Consequences of BEST1 Gene Mutations in Canine Multifocal Retinopathy Predict Functional Implications for Human Bestrophinopathies. Invest Ophthalmol Vis Sci 52:4497-505, 2011.

Guziewicz KE, Zangerl B, Lindauer SJ, Mullins RF, Sandmeyer LS, Grahn BH, Stone EM, Acland GM, Aguirre GD. Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. Invest Ophthalmol Vis Sci 48:1959-67, 2007.

Zangerl B, Wickström K, Slavik J, Lindauer SJ, Ahonen S, Schelling C, Lohi H, Cuziewicz KE, Aguirre GD. Assessment of canine BEST1 variations identifies new mutations and establishes an independent bestrophinopathy model (cmr3). Mol Vis 16:2791-2804, 2010.

15. Canine Scott Syndrome

Disease Category Type
blood

Description
Canine Scott Syndrome (CSS) is a bleeding disorder found in German Shepherd Dogs. The disease is caused by hereditary platelet dysfunction leading to abnormally slow clot formation at the site of vascular injury. The disease presents itself most commonly as abnormal bleeding after surgical intervention. Some dogs may have nontraumatic nosebleeds or hemorrhage into joints or soft tissues. The inheritance pattern is autosomal recessive.

Clinical Overview
The most common clinical sign of the disease is postoperative bruising and hematoma formation at surgical sites. The symptoms are usually mild but life-threatening bleeding following surgery has been reported. Nonsurgical bleeds may also occur and include potentially recurrent episodes of epistaxis (nosebleeds) and hemorrhage into joints or soft tissues. Petechiae of the gums has not been reported as a symptom. The disease is caused by a defect in the transportation of phosphatidylserine to the surface of activated platelets. There is no cure. Treatment with blood or platelet transfusions is performed as necessary.

Mutation Found In:
German Shepherd Dog

Gene Variant Tested
ANO6 German Shepherd Dog

Clinical Signs
excessive bleeding after surgery, nosebleed, nontraumatic hemorrhage

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Brooks M, Catalfamo J, MacNguyen R, Tim D, Fancher S, McCardle J. A TMEM16F Point Mutation Causes an Absence of Canine Platelet TMEM16F and Ineffective Activation and Death-Induced Phospholipid Scrambling. J Thrombosis and Haemostasis Dec;13(12):2240-2252, 2015.

Jandrey K, Norris J, Tucker M, Brooks M. Clinical Characterization of Canine Platelet Procoagulant Deficiency (Scott Syndrome). J Vet Int Med Nov/Dec;26(6):1402-1407, 2012.

16. Cavalier King Charles Spaniel Muscular Dystrophy, (CKCS-MD)

Disease Category Type
muscular

Description
Duchenne or dystrophin muscular dystrophy (DMD) is a severe X-linked disorder that causes muscle degeneration and formation of excess connective tissue. DMD is characterized by spinal curvature and a crouched posture. Due to the X-linked recessive mode of inheritance, mainly males are affected, although some female carriers were suggested to suffer from less severe muscle weakness. The disorder is caused by several different mutations in the dystrophin gene; this variant is associated with causing the condition in Cavalier King Charles Spaniels. Affected puppies are usually euthanized at a young age because of the severity of the disorder.

Clinical Overview
Duchenne muscular dystrophy results from sarcolemma (cell membrane of striated muscle fiber cells) dysfunction which causes degeneration and necrosis of muscle tissue. DMD is a progressive condition that eventually leads to muscle fibrosis (formation of excess fibrous connective tissue). First signs of disease, such as bunny-hopping gate, can be observed in eight to ten weeks old puppies. Affected puppies have a thick tongue base and are unable to open the mouth properly which causes eating difficulties and excess drooling. Duchenne muscular dystrophy is characterized by crouched posture caused by spinal curvature and bending of the back. Serum creatine kinase concentrations can be over 300 times higher than normal levels. Affected puppies are usually euthanized at a young age because of the severity of the disorder.

Mutation Found In:
Cavalier King Charles Spaniel, King Charles Spaniel, English Toy Spaniel

Gene Variant Tested
Dystrophin CKCS

Clinical Signs
muscle fibrosis, high serum creatine kinase concentration, spinal curvature, crouched posture, thick tongue base, and excessive salivation

Mode of Inheritance
X-linked

Signs Seen in Affected Carriers
less severe muscle weakness

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kornegay, JN., Bogan, JR., Bogan, DJ., Childers, MK., Grange, RW. Golden retriever muscular dystrophy (GRMD): Developing and maintaining a colony and physiological functional measurements. Methods Mol Biol 709:105-23, 2011.

Cooper BJ, Winand NJ, Stedman H, Valentine BA, Hoffman EP, Kunkel LM, Scott MO, Fischbeck KH, Kornegay JN, Avery RJ, Williams JR, Schmickel RD, Sylvester JE. The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs. Nature 334:154-156, 1988.

Sharp NJH, Kornegay JN, Vancamp SD, Herbstreith MH, Secore SL, Kettle, S, Hung WY, Constantinou CD, Dykstra MJ, Roses AD, Bartlett RJ. An Error in Dystrophin Messenger RNA Processing in Golden Retriever Muscular Dystrophy, an Animal Homologue of Duchenne Muscular Dystrophy. Genomics 13:115-121, 1992.

Smith BF, Yue Y, Woods PR, Kornegay JN, Shin JH, Williams RR, Duan D. An intronic LINE-1 element insertion in the dystrophin gene aborts dystrophin expression and results in Duchenne-like muscular dystrophy in the corgi breed. Lab Invest 91:216-31, 2011.

Walmsley GL, Arechavala-Gomeza V, Fernandez-Fuente M, Burke MM, Nagel N, Holder A, Stanley R, Chandler K, Marks SL, Muntoni F, Shelton GD, Piercy RJ. A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping. PLoS One 5:e8647, 2010.

17. Centronuclear Myopathy, (CNM); mutation originally found in Great Dane

Disease Category Type
muscular

Description
Centronuclear myopathy (CNM) is a type of muscle disease; this variant is found in Great Danes. The severity of the clinical signs and age of onset varies, but common manifestations are muscle weakness and skeletal muscle atrophy causing exercise intolerance and posture abnormalities. The inheritance pattern is autosomal recessive.

Clinical Overview
The onset and progression of CNM varies among individuals and breeds. In Great Danes, typical clinical signs of CNM are general atrophy of the muscles, exercise intolerance, and exercise-related tremors of the muscles. Typically clinical signs appear at 6 to 8 months of age and progress with age. Most affected dogs will need to be euthanized before the age of 18 months due to severe weakness of the muscles.

Mutation Found In:
Great Dane

Gene Variant Tested
BIN1

Clinical Signs
muscle weakness, exercise intolerance, ventroflexion, and skeletal muscle atrophy

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Böhm J, Vasli N, Maurer M, Cowling BS, Shelton GD, Kress W, Toussaint A, Prokic I, Schara U, Anderson TJ, Weis J, Tiret L, Laporte J. Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy. PLoS Genet 9(6): e1003430, 2013.

Gentilini F, Zambon E, Gandini G, Rosati M, Spadari A, Romagnoli N, Turba ME, Gernone F. Frequency of the allelic variant of the PTPLA gene responsible for centronuclear myopathy in Labrador Retriever dogs as assessed in Italy. J Vet Diagn Invest 23:124-6, 2011.

Pelé M, Tiret L, Kessler JL, Blot S, Panthier JJ. SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Hum Mol Genet n14:1417-27, 2005.

18. Centronuclear Myopathy, (CNM); mutation originally found in Labrador Retriever

Disease Category Type
muscular

Description
Centronuclear myopathy (CNM) is a type of muscle disease; this variant is found in Labrador Retrievers. The severity of the clinical signs and age of onset varies, but common manifestations are muscle weakness and skeletal muscle atrophy causing exercise intolerance and posture abnormalities. The inheritance pattern is autosomal recessive.

Clinical Overview
The onset and progression of CNM varies among individuals and breeds. In Labrador Retrievers, weakened or non-existent peripheral reflexes of the legs can occasionally be observed as early as 1 month of age, although more typically not until the puppies are 2 to 5 months old. At the age of 5 months, the affected puppies manifest diminished locomotion and exercise intolerance. The condition does not usually progress after the first year of life. In adult dogs, the most common signs are severe skeletal muscle atrophy especially in the areas of head, neck, and legs that limit the dog's ability to keep his head raised (ventroflexion) as well as abnormalities in posture and movements. Although the disorder limits the dog's athletic potential, it can still have a normal life span as a pet.

Mutation Found In:
Labrador Retriever

Gene Variant Tested
PTPLA

Clinical Signs
muscle weakness, exercise intolerance, ventroflexion, and skeletal muscle atrophy

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Böhm J, Vasli N, Maurer M, Cowling BS, Shelton GD, Kress W, Toussaint A, Prokic I, Schara U, Anderson TJ, Weis J, Tiret L, Laporte J. Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy. PLoS Genet 9(6): e1003430, 2013.

Gentilini F, Zambon E, Gandini G, Rosati M, Spadari A, Romagnoli N, Turba ME, Gernone F. Frequency of the allelic variant of the PTPLA gene responsible for centronuclear myopathy in Labrador Retriever dogs as assessed in Italy. J Vet Diagn Invest 23:124-6, 2011.

Pelé M, Tiret L, Kessler JL, Blot S, Panthier JJ. SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Hum Mol Genet 14:1417-27, 2005.

19. Cerebellar Cortical Degeneration, (CCD); mutation originally found in Vizsla

Disease Category Type
neurologic

Description
Cerebellar cortical degeneration or cerebellar abiotrophy is encountered in several dog breeds. Cerebellar abiotrophy is characterized by progressive degeneration of neurons in the cerebellar cortex. An affected dog suffers from ataxia (uncoordinated movements) with abnormal length of movement. The age of onset and the progression of clinical signs seem to vary in affected breeds due to different causative mutations. The disorder caused by this mutation in Vizslas is inherited as an autosomal recessive trait.

Clinical Overview
The typical signs of cerebellar cortical degeneration typically emerge at 2-3 months of age. The clinical signs include progressive cerebellar ataxia, exaggerated movements, loss of balance, and a dysmetric gait with the inability to regulate rate and range of movement. Affected dogs can have intention tremors and nystagmus. The affected puppies have a normal state of alertness.

Mutation Found In:
Vizsla, Wirehaired Vizsla

Gene Variant Tested
SNX14

Clinical Signs
loss of coordination of movement, loss of balance, intention tremors

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Fenn J, Boursnell M, Hitti R, Jenkins C, Terry R, Priestnall S, Kenny P, Mellersh C, Forman O. Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed. BMC Genetics 201617:123. DOI: 10.1186/s12863-016-0433-y

20. Cerebellar Hypoplasia; mutation originally found in Eurasier

Disease Category Type
neurologic

Description
Cerebellar hypoplasia in Eurasier dogs resembles the human Dandy-Walker malformation. Affected dogs are presented with non-progressive ataxia of varying severity. The disease results from uniform cerebellar malformation with absence of the cerebellar vermis and caudal portions of the cerebellar hemispheres associated with large retrocerebellar fluid accumulations. The inheritance pattern is autosomal recessive and the condition is not curable. Other breeds that have been shown to exhibit a similar condition include the Chow Chow, Boston Terrier, Bull Terrier, Airedale Terrier, Weimaraner, Shih Tzu, Dachshund, Miniature Schnauzer, and Labrador Retriever. With the exception of the Chow Chow, the genetic background of these breeds differs from the Eurasier, so it is not known if the causal mutation in the Eurasier is responsible for the condition in these other breeds.

Clinical Overview
Clinical signs of cerebellar hypoplasia include ataxia of varying severity, from mild truncal sway and subtly uncoordinated gait to severe cerebellar ataxia and falling or rolling. Some dogs may exhibit epileptic seizures, nystagmus, or tremors. Clinical signs are present from birth and are typically noticed when puppies start to walk. Affected dogs will lack a menace reflex. The most severely affected puppies are usually euthanized. Some dogs exhibit only minor ataxia in adulthood. There is no cure and treatment is symptomatic and palliative. It is estimated that 16% of Eurasier dogs are carriers of the disease.

Mutation Found In:
Eurasier

Gene Variant Tested
VLDLR Eurasier

Clinical Signs
ataxia of varying severity, epileptic seizures, cerebellar hypoplasia

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gerber M, Fischer A, Jagannathan V, Drögemuller M, Drögemuller C, Schmidt M, Bernandino F, Manz E, Matiasek K, Rentmeister K, Leeb T. A deletion in the VLDLR gene in Eurasier dogs with cerebellar hypoplasia resembling a Dandy-Walker-like malformation (DWLM). PLoS ONE 10(2): e0108917, 2015.

Bernardino F, Rentmeister K, Schmidt M, Bruehschwein A, Matiasek K, Matiasek L, Lauda A, Schoon H, Fischer A. Inferior cerebellar hypoplasia resembling a Dandy-Walker like malformation in purebred Eurasier dogs with familial non-progressive ataxia: a retrospective and prospective clinical cohort study. PLoS ONE 10(2): e0117670, 2015.

21. Cerebral Dysfunction; mutation originally found in Frisian Stabyhoun

Disease Category Type
neurologic

Description
Severe cerebral dysfunction has been reported in Frisian Stabyhoun puppies. Affected puppies exhibit severe, progressive cerebral signs leading to euthanasia before they reach 4 months of age. The disease is caused by altered function of the dopamine transporter. The mode of inheritance is autosomal recessive.

Clinical Overview
The disease causes severe, progressing cerebral signs including mental depression, excessive sniffing and circling, walking backwards, and limb weakness. Affected puppies are euthanized before 4 months of age. Affected puppies do not exhibit any abnormalities in routine blood work, cerebrospinal fluid analysis, or magnetic resonance imaging.

Mutation Found In:
Frisian Stabyhoun (Pointer)

Gene Variant Tested
SLC6A3 Frisian Stabyhoun

Clinical Signs
depression, circling, excessive sniffing, limb weakness

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Arata S, Ogata N, Shimozuru M, Takeuchi Y, Mori Y. Sequences and polymorphisms of the canine monoamine transporter genes SLC6A2, SLC6A3, and SLC6A4 among five dog breeds. J Vet Med Sci. 2008 Sep;70(9):971-5.

22. Chondrodysplasia; mutation originally found in Norwegian Elkhound and Karelian Bear Dog

Disease Category Type
skeletal

Description
Chondrodysplasia encompasses a group of skeletal disorders caused by abnormalities in cartilage growth and ossification, which manifest as disproportionate dwarfism of the limbs. The causative mutation was first identified in Norwegian Elkhounds and later in Karelian Bear Dogs and Chinooks. The disease is inherited in an autosomal recessive manner.

Clinical Overview
Dogs affected by chondrodysplasia are 10 to 15 cm shorter in height than other individuals of the same breed. Affected dogs have short limbs and support more of their weight on their front limbs, resulting in the outward bend noted in the forelimbs of these dogs. Disproportionate growth (short limbs, normal sized body and head) can be observed as early as one week of age.

Mutation Found In:
Chinook, Karelian Bear Dog, Norwegian Elkhound

Gene Variant Tested
ITGA10

Clinical Signs
shortened limbs

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kyöstilä K, Lappalainen AK, Lohi H. Canine chondrodysplasia caused by a truncating mutation in collagen-binding integrin alpha subunit 10. PLoS One 8(9):e75621, 2013.

Bingel SA, Sande RD. Chondrodysplasia in the Norwegian Elkhound. Am J Pathol 107(2):219-229, 1982.

Donner J, Kaukonen M, Anderson H, Möller F, Kyöstilä K, Sankari S, Hytönen M, Giger U, Lohi H. Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders. PLoS One. 2016 Aug 15;11(8):e0161005.

23. Cleft Lip and Palate with Syndactyly; ADAMTS20 gene mutation originally found in Nova Scotia Duck Tolling Retriever

Disease Category Type
skeletal

Description
A cleft palate is an abnormal hole in the roof (palate) of the mouth which results in an opening between the nasal passages and the oral cavity through which milk passes when an affected puppy is nursing. Though cleft palate can occur in many breeds, this mutation, found in the Nova Scotia Duck Tolling Retriever is associated with additional birth defects. Affected puppies can have a small lower jaw in addition to the cleft palate. Furthermore, this more complex form of cleft palate can also include cleft lip and syndactyly (joined digits) in this breed. The disorder is inherited as autosomal recessive traits.

Clinical Overview
Cases that are affected by this more complex syndrome will exhibit a cleft palate but may also have a cleft lip and evidence of fused digits, as the condition's name suggests.

Mutation Found In:
Nova Scotia Duck Tolling Retriever

Gene Variant Tested
ADAMTS20

Clinical Signs
cleft in the roof of the mouth and food matter noted in the nasal passages, cleft lip, joined digits

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wolf ZT, Leslie EJ, Arzi B, Jayashankar K, Karmi N, Jia Z, Rowland DJ, Young A, Safra N, Sliskovic S, Murray JC, Wade CM, Bannasch DL. A LINE-1 Insertion in DLX6 Is Responsible for Cleft Palate and Mandibular Abnormalities in a Canine Model of Pierre Robin Sequence. PLoS Genet10:e1004257, 2014.

Wolf ZT, Brand HA, Shaffer JR, Leslie EJ, Arzi B, Willet CE, Cox TC, McHenry T, Narayan N, Feingold E, Wang X, Sliskovic S, Karmi N, Safra N, Sanchez C, Deleyiannis FW, Murray JC, Wade CM, Marazita ML, Bannasch DL. Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate. PLoS Genet. Mar 23;11(3):e1005059, 2015.

24. Cleft Palate; DLX6 gene mutation originally found in Nova Scotia Duck Tolling Retriever

Disease Category Type
skeletal

Description
Cleft palate is a birth defect encountered in several breeds. A cleft palate is an abnormal hole in the roof (palate) of the mouth which results in an opening between the nasal passages and the oral cavity through which milk passes when an affected puppy is nursing. An inherited form of cleft palate associated with a small lower jaw is known to affect the Nova Scotia Duck Tolling Retriever. The disorders are inherited as autosomal recessive traits.

Clinical Overview
The palate is the roof of the mouth separating the oral cavity and nasal passages. A cleft palate is a result of failure of the two sides of the palate to come together and fuse during embryonic development. A cleft palate forms an opening between the mouth and nasal passages, allowing milk to flow into the nasal passages when an affected puppy is nursing. A cleft palate causes feeding difficulties that can lead to decreased growth. When an affected puppy is nursing, milk can be seen spilling out from its nostrils or the puppy may try to gag out milk from its lower respiratory tract. Milk entering the nasal passages often leads to chronic infection. A cleft palate will greatly increase the risk of affected puppies developing aspiration pneumonia. Puppies suffering from severe cleft palate are unlikely to survive through puppyhood without proper treatment. A cleft palate can be operated on when a puppy is 3-4 months old. Puppies with severe symptoms may need tube feeding to survive until the operation can be performed.

Mutation Found In:
Nova Scotia Duck Tolling Retriever

Gene Variant Tested
DLX6

Clinical Signs
cleft in the roof of the mouth and food matter noted in the nasal passages

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wolf ZT, Leslie EJ, Arzi B, Jayashankar K, Karmi N, Jia Z, Rowland DJ, Young A, Safra N, Sliskovic S, Murray JC, Wade CM, Bannasch DL. A LINE-1 Insertion in DLX6 Is Responsible for Cleft Palate and Mandibular Abnormalities in a Canine Model of Pierre Robin Sequence. PLoS Genet10:e1004257, 2014.

Wolf ZT, Brand HA, Shaffer JR, Leslie EJ, Arzi B, Willet CE, Cox TC, McHenry T, Narayan N, Feingold E, Wang X, Sliskovic S, Karmi N, Safra N, Sanchez C, Deleyiannis FW, Murray JC, Wade CM, Marazita ML, Bannasch DL. Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate. PLoS Genet. Mar 23;11(3):e1005059, 2015.

25. Color Locus H (PSMB7 gene): Harlequin (H allele)

Disease Category Type
other

Description
The harlequin coat pattern results from the interaction of two genes: the dominant melanosomal gene, SILV, which causes the merle pattern, and the modifier gene, harlequin (H). This pattern is most recognized in the Harlequin Great Dane where eumelanin pigment expressing the SILV gene is turned white instead of appearing gray as in a coat only exhibiting merling. The harlequin gene creates the white patches that contrast against the coat areas that are not expressing SILV (merle) and express pigment. The harlequin gene is an autosomal dominant gene; homozygous individuals die in utero.

Clinical Overview
The merle gene randomly dilutes sections of the coat to a lighter color (ex. black to gray). In the Great Dane, this pattern is modified by the harlequin gene which makes the lighter areas pure white, resulting in a random, patchy appearance of dark pigment interspersed with white areas. The gene will affect both the eumelanin and phaeomelanin pigments. The harlequin gene requires the merle gene to function. All harlequins have been shown to be heterozygous for the gene suggesting that it is a homozygous lethal trait in utero.

Mutation Found In:
Great Dane

Gene Variant Tested
PSMB7

Clinical Signs
a coat with ragged, patches of full color on a white background

Mode of Inheritance
autosomal dominant

Disease Severity
severe discomfort in homozygote

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Clark, LA, Tsai, KL, Starr, AN, Nowend, KL, Murphy, KE. A missense mutation in the 20S proteasome ?2 subunit of Great Danes having harlequin coat patterning. Genomics. 2011 Apr;97(4):244-8.

Clark, LA, Starr, AN, Tsai, KL, Murphy, KE. Genome-wide linkage scan localizes the harlequin locus in the Great Dane to chromosome 9. Gene. 2008 Jul 15;418(1-2):49-52.

26. Complement 3 (C3) Deficiency

Disease Category Type
immunologic

Description
Complement 3 (C3) deficiency is a disease that causes severe immunodeficiency in the Brittany. The disease follows autosomal recessive inheritance. Treatment with antibiotics is supportive but not curative.

Clinical Overview
C3 plays a critical role in the immune system. Deficiency in C3 predisposes an affected puppy to recurrent bacterial infections at an early age and to renal amyloidosis or Type 1 membranoproliferative glomerulonephritis. C3 deficient puppies also have an increased risk of developing hereditary renal and muscular disease (familial juvenile glomerulonephropathy and hereditary canine spinal muscular atrophy). Treatment with antibiotics is supportive but not curative.

Mutation Found In:
Brittany

Gene Variant Tested
C3

Clinical Signs
recurrent bacterial infections and renal disease

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Johnson JP, McLean RH, Cork LC, Winkelstein JA. Genetic analysis of an inherited deficiency of the third component of complement in Brittany spaniel dogs. Am J Med Genet 25:557-562, 1986.

Ameratunga R, Winkelstein JA, Brody L, Binns M, Cork LC, Colombani P, Valle D. Molecular analysis of the third component of canine complement (C3) and identification of the mutation responsible for hereditary canine C3 deficiency. J Immunol 160:2824-30, 1998.

27. Cone Degeneration, (CD) or Achromatopsia; mutation originally found in Alaskan Malamute

Disease Category Type
ocular

Description
Cone degeneration (CD), also called "day-blindness" is an inherited eye disorder causing photophobia and an inability to see in bright light. The disease is inherited through an autosomal recessive pattern of inheritance.

Clinical Overview
Clinical signs of CD occur at the age of 8-12 weeks. Affected pups show signs of day-blindness and photophobia due to the degeneration of cone cells in the retina. Cone cells are completely absent in an adult dog affected with CD. The degeneration does not affect rod cells, therefore vision in dim light remains normal; cone degeneration does not result in blindness.

Mutation Found In:
Alaskan Malamute, Australian Shepherd, Miniature American Shepherd

Gene Variant Tested
CNGB3 deletion

Clinical Signs
day-blindness and photophobia

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Sidjanin DJ, Lowe JK, McElwee JL, Milne BS, Phippen TM, Sargan DR, Aguirre GD, Acland GM, Ostrander EA. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet 11(16):1823-33, 2002.

Yeh CY, Goldstein O, Kukekova AV, Holley D, Knollinger AM, Huson HJ, Pearce-Kelling SE, Acland GM, Komáromy AM. Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia. BMC Genet 14:27, 2013.

28. Cone Degeneration, (CD) or Achromatopsia; mutation originally found in German Shepherd Dog

Disease Category Type
ocular

Description
Cone degeneration (CD), also called "day-blindness is an inherited eye disorder causing photophobia and an inability to see in bright light. The disease is inherited through an autosomal recessive pattern of inheritance.

Clinical Overview
Clinical signs of CD occur at the age of 8-12 weeks. Affected pups show signs of day-blindness and photophobia due to the degeneration of cone cells in the retina. Cone cells are completely absent in an adult dog affected with CD. The degeneration does not affect rod cells, therefore vision in dim light remains normal; cone degeneration does not result in blindness.

Mutation Found In:
German Shepherd Dog

Gene Variant Tested
CNGA3 German Shepherd Dog

Clinical Signs
day-blindness and photophobia

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Sidjanin DJ, Lowe JK, McElwee JL, Milne BS, Phippen TM, Sargan DR, Aguirre GD, Acland GM, Ostrander EA. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet 11(16):1823-33, 2002.

Yeh CY, Goldstein O, Kukekova AV, Holley D, Knollinger AM, Huson HJ, Pearce-Kelling SE, Acland GM, Komáromy AM. Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia. BMC Genet 14:27, 2013.

29. Cone Degeneration, (CD) or Achromatopsia; mutation originally found in German Shorthaired Pointer

Disease Category Type
ocular

Description
Cone degeneration (CD), also called "day-blindness" is an inherited eye disorder causing photophobia and an inability to see in bright light. The disease is inherited through an autosomal recessive pattern of inheritance.

Clinical Overview
Clinical signs of CD occur at the age of 8-12 weeks. Affected pups show signs of day-blindness and photophobia due to the degeneration of cone cells in the retina. Cone cells are completely absent in an adult dog affected with CD. The degeneration does not affect rod cells, therefore vision in dim light remains normal; cone degeneration does not result in blindness.

Mutation Found In:
German Shorthaired Pointer

Gene Variant Tested
CNGB3 German Shorthaired Pointer

Clinical Signs
day-blindness and photophobia

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Sidjanin DJ, Lowe JK, McElwee JL, Milne BS, Phippen TM, Sargan DR, Aguirre GD, Acland GM, Ostrander EA. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet 11(16):1823-33, 2002.

Yeh CY, Goldstein O, Kukekova AV, Holley D, Knollinger AM, Huson HJ, Pearce-Kelling SE, Acland GM, Komáromy AM. Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia. BMC Genet 14:27, 2013.

30. Cone-Rod Dystrophy 1, (crd1); mutation originally found in American Staffordshire Terrier

Disease Category Type
ocular

Description
Cone-rod dystrophy is an eye disorder resulting in retinal degradation at a young age and occurs in several different forms in various different dog breeds. Cone-rod dystrophy 1 (crd1) is found in American Staffordshire Terriers and the disorder has an autosomal recessive pattern of inheritance.

Clinical Overview
The clinical picture for crd1 is that of a progressive eye disorder that typically causes retinal cell degradation and thinning of the retina, often visible at 3-6 months of age. The onset of the disorder involves the reduction of cone cells required for day vision and continues with the reduction of rod cells necessary for night vision. Typically, clinical signs of this fast-progressing disease will appear in puppyhood and vision will be severely affected by one year of age, leading to blindness in the juvenile dog. crd1 can be suspected in a dog based on the breed and can be confirmed by performing a fundic exam to evaluate the retina. Diagnosis is usually obtained by ophthalmoscopy.

Mutation Found In:
American Staffordshire Terrier, Mixed breed

Gene Variant Tested
PDE6B American Staffordshire Terrier

Clinical Signs
severe retinal degeneration and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Goldstein O, Mezey JG, Schweitzer PA, Boyko AR, Gao C, Bustamante CD, Jordan JA, Aguirre GD, Acland GM. IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds. Invest Ophthalmol Vis Sci54:7005-19, 2013.

31. Cone-Rod Dystrophy 2, (crd2); mutation originally found in American Pit Bull Terrier

Disease Category Type
ocular

Description
Cone-rod dystrophy 2 (crd2) is an inherited, early-onset eye disorder characterized by retinal degeneration. Several forms of cone-rod dystrophy have been encountered in various breeds. Cone-rod dystrophy 2 affects American Pit Bull Terriers. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
crd2 is a progressive eye disorder characterized by degeneration of photoreceptor cells and retinal thinning at a young age. The first observable clinical sign is vision loss in daylight caused by degeneration of cone cells. This is followed by loss of rod cells required for vision in dim light. The condition progresses rapidly and the loss of vision is usually noticed in puppyhood. Retinal degeneration in crd2 generally leads to severe loss of vision by one year of age and to total blindness in early adulthood. Retinal changes are usually observable by 3-6 months of age.

Mutation Found In:
American Pit Bull Terrier

Gene Variant Tested
IQCB1

Clinical Signs
severe retinal degeneration and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Goldstein O, Mezey JG, Schweitzer PA, Boyko AR, Gao C, Bustamante CD, Jordan JA, Aguirre GD, Acland GM. IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds. Invest Ophthalmol Vis Sci54:7005-19, 2013.

32. Cone-Rod Dystrophy, Standard Wirehaired Dachshund, (crd SWD)

Disease Category Type
ocular

Description
This type of cone-rod dystrophy (crd SWD) is a form of progressive retinal atrophy affecting Wirehaired Dachshunds of all sizes but was first found in the Standard size. Gradual loss of photoreceptors eventually leads to blindness in affected dogs. Cone-rod dystrophy SWD is inherited in an autosomal recessive manner.

Clinical Overview
Cone-rod dystrophy (crd SWD) is an eye disorder with gradual degeneration of photoreceptors, which eventually leads to blindness. The disease first affects cone cells and only later the rod cells. Ocular fundus changes, such as an initial cellophane-like increase in the tapetal area and pigment migration from the non-tapetal region, are observed. The age of onset of crd SWD varies from 10 months to 3 years, although affected puppies can be recognized as early as 5 to 10 weeks of age by the presence of pinpoint sized pupils upon examination with focal light. The disease leads to blindness within 6 years from the time signs are first noted. No treatment is available for crd SWD.

Mutation Found In:
Standard Wirehaired Dachshund, Miniature Wirehaired Dachshund

Gene Variant Tested
NPHP4

Clinical Signs
loss of vision and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Ropstad EO, Bjerk's E, Narfström K. Clinical findings in early onset cone-rod dystrophy in the Standard Wire-haired Dachshund. Vet Ophthalmol 10(2):69-75, 2007.

Wiik AC, Wade C, Biagi T, Ropstad EO, Bjerk's E, Lindblad-Toh K, Lingaas F. A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund. Genome Res 18(9):1415-1421, 2008.

33. Congenital Hypothyroidism; mutation originally found in Tenterfield Terrier

Disease Category Type
endocrine

Description
Acquired hypothyroidism is common in middle aged and older dogs. In addition to the acquired form of the disease, congenital hypothyroidism is also encountered in dogs, but is more rare. The clinical signs of the congenital form are very different from those of the acquired form. The tested mutation causes hypothyroidism in Tenterfield Terriers, where it is inherited in an autosomal recessive manner. The results from this test cannot be applied to other breeds.

Clinical Overview
Affected puppies appear normal at birth, with slowed growth usually observed around 3 to 8 weeks of age. Disproportionate dwarfism is typical for affected puppies: they have wide heads, short and thick necks, and short limbs. Affected puppies show mental impairment and their puppy coats are not replaced with the adult coat. Delayed opening of eyes and ear canals and delayed teething may be observed. Goiter (swelling and enlargement of the thyroid gland) is also observed. The disease may lead to death during the first weeks of life.

Mutation Found In:
Tenterfield Terrier

Gene Variant Tested
TPO Tenterfield Terrier

Clinical Signs
slow growth, drowsiness, disproportionate dwarfism, goiter, mental impairment, and abnormal hair coat

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Bojanic K, Acke E, Jones B. Congenital hypothyroidism of dogs and cats: A review. N Z Vet J 59:115-122, 2011.

Dodgson SE, Day R, Fyfe JC. Congenital hypothyroidism with goiter in Tenterfield terriers. J Vet Intern Med 26(6):1350-1357, 2012.

Fyfe JC, Kampschmidt K, Dang V, Poteet BA, He Q, Lowrie C, Graham PA, Fetro VM. Congenital hypothyroidism with goiter in toy fox terriers. J Vet Intern Med 17:50-57, 2003.

Fyfe JC, Lynch M, Olsen J, Lou?r E. A thyroid peroxidase (TPO) mutation in dogs reveals a canid-specific gene structure. Mamm Genome 24(3-4):127-133, 2013.

Pettigrew R, Fyfe JC, Gregory BL, Lipsitz D, Delahunta A, Summers BA, Shelton GD. CNS hypomyelination in Rat Terrier dogs with congenital goiter and a mutation in the thyroid peroxidase gene. Anim Vet Pathol 44:50-6, 2007.

34. Congenital Myasthenic Syndrome, (CMS); mutation originally found in Jack Russell Terrier

Disease Category Type
neuromuscular

Description
Congenital myasthenic syndrome (CMS) is a neuromuscular disorder originally identified in the Jack Russell Terrier. Several mutations have been found to give rise to similar clinical signs in various breeds. A mutated CHRNE gene has been identified as also causing CMS in the Jack Russell Terrier. The mutation results in a substantial reduction of acetylcholine receptor protein content and affected individuals exhibit muscle weakness. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Initial signs of congenital myasthenic syndrome can be observed in 12-16 weeks old puppies. Affected dogs suffer from exercise intolerance and collapse after 5-30 minutes of exercise. Before collapsing, affected dogs will start to take shorter and shorter strides and eventually fall down. Affected dogs are able to recover from the transient paralysis after resting for a few minutes, but the signs reappear if the dog continues to run. The disorder is inherited in an autosomal recessive manner.

Mutation Found In:
Jack Russell Terrier

Gene Variant Tested
CHRNE

Clinical Signs
temporary collapse/paralysis induced by exercise

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Rinz CJ, Lennon VA, James F, Thoreson JB, Tsai KL, Starr-Moss AN, Humphries HD, Guo LT, Palmer AC, Clark LA, Shelton GD. A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers. Neuromuscul Disord. 2015 Dec;25(12):921-7.

35. Congenital Myasthenic Syndrome, (CMS); mutation originally found in Labrador Retriever

Disease Category Type
neuromuscular

Description
Congenital myasthenic syndrome (CMS) is a neuromuscular disorder originally identified in Old Danish Pointing Dogs. This particular mutation was identified in the Labrador Retriever and is associated with a more severe form of CMS. Symptoms involve generalized neuromuscular disease with short-strided tetraparesis that worsens with exercise. Symptoms are present at a very young age. Muscle weakness results from a defect in the synthesis of acetylcholinesterase. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Initial signs of congenital myasthenic syndrome can be observed in 12-16 weeks old puppies. Affected dogs suffer from exercise intolerance and collapse after 5-30 minutes of exercise. Before collapsing, affected dogs will start to take shorter and shorter strides and eventually fall down. Affected dogs are able to recover from the transient paralysis after resting for a few minutes, but the signs reappear if the dog continues to run. The disorder is inherited in an autosomal recessive manner.

Mutation Found In:
Labrador Retriever

Gene Variant Tested
COLQ

Clinical Signs
temporary collapse/paralysis induced by exercise

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Rinz CJ, Levine J, Minor KM, Humphries HD, Lara R, Starr-Moss AN, Guo LT, Williams DC, Shelton GD, Clark LA. A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome. PLoS One. 2014 Aug 28;9(8):e106425.

36. Congenital Myasthenic Syndrome, (CMS); mutation originally found in Old Danish Pointing Dog

Disease Category Type
neuromuscular

Description
Congenital myasthenic syndrome (CMS) is a neuromuscular disorder affecting Old Danish Pointing Dogs. Exercise intolerance manifests as affected dogs collapsing during exercise. Muscle weakness results from a defect in the synthesis of the neurotransmitter acetylcholine. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Initial signs of congenital myasthenic syndrome can be observed in 12-16 weeks old puppies. Affected dogs suffer from exercise intolerance and collapse after 5-30 minutes of exercise. Before collapsing, affected dogs will start to take shorter and shorter strides and eventually fall down. Affected dogs are able to recover from the transient paralysis after resting for a few minutes, but the signs reappear if the dog continues to run. The disorder is inherited in an autosomal recessive manner.

Mutation Found In:
Old Danish Pointing Dog

Gene Variant Tested
CHAT

Clinical Signs
temporary collapse/paralysis induced by exercise

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Proschowsky HF, Flagstad A, Cirera S, Joergensen CB, Fredholm M Identification of a mutation in the CHAT gene of Old Danish Pointing Dogs affected with congenital myasthenic syndrome. J Hered. 98(5):539-543, 2007.

37. Craniomandibular Osteopathy, (CMO); mutation associated with terrier breeds

Disease Category Type
skeletal

Description
Craniomandibular osteopathy (CMO, "lion's jaw") is a disorder of skull and jaw bones that mainly affects some terrier breeds, such as Cairn Terrier, Scottish Terrier, and West Highland White Terrier. Recent studies indicate that the mode of inheritance for this particular mutation may be different from previously reported and that the disease most closely follows an autosomal dominant pattern of inheritance with incomplete penetrance in the West Highland White Terrier. However, despite the dominant pattern of inheritance, even dogs with two copies of the mutation may not develop clinical signs due to the incomplete penetrance. Non-terrier breeds diagnosed with CMO may be expressing a different mutation.

Clinical Overview
The first clinical signs of CMO typically appear at the age of 4 to 7 months. The skull bones and especially the mandible seem enlarged due to swelling and thickening of the jaw. The condition causes pain, which manifests in drooling, difficulties in eating, and unwillingness to open mouth. In addition, recurrent fever may be associated with CMO. Bone changes may disappear once the dog's growth period is finished, but before that multiple episodes of fever and pain may occur.

Mutation Found In:
Cairn Terrier, Scottish Terrier, West Highland White Terrier

Gene Variant Tested
SLC37A2

Clinical Signs
swelling and thickening of the jaw, difficulties in chewing, pain, and recurrent fever

Mode of Inheritance
autosomal dominant

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Hytönen M, Arumilli M, Lappalainen A, Owczarek-Lipska M, Jagannathan V, Hundi S, Salmela E, Venta P, Sarkiala E, Jokinen T, Gorgas D, Kere J, Nieminen P, Drögemüller C, Lohi H. Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes. PLOS Genetics. 2016 May 17;12(5):e1006037.

Alexander, JW. Selected skeletal dysplasia: Craniomandibular osteopathy, multiple cartilaginous exostosis, and hypertrophic osteodystrophy. Vet Clin North America: Small Animal 13:55 70, 1983.

Riser, W, Newton, CD. "Craniomandibular osteopathy. Textbook of Small Animal Orthopedics. Ed. Newton, CD, Nunamaker, DM. Philadelphia: Lippincott Co, 1985. 621-626. Print.

Watson, ADJ, Adams, WM, Thomas, CB. Craniomandibular osteopathy in dogs. Compendium Vet Med Small Animal (July): 911 922, 1995.

LaFond, E, Breur, GJ, Austin, CC. Breed susceptibility for developmental orthopedic diseases in dogs. Jour American Animal Hosp Assoc 38:467 477, 2002.

Schwarz, T, Weller, R, Dickie, AM, Konar, M, Sullivan, M. Imaging of the canine and feline temporomandibular joint: A review. Vet Radiol Ultrasound 43: 85 97, 2002.br>

38. Cystinuria Type I-A; mutation originally found in Newfoundland Dog

Disease Category Type
renal

Description
Dogs with cystinuria are not able to reabsorb the amino acid cystine in their kidneys and therefore high concentrations can accumulate in the urinary tract causing formation of cystine crystals and stones that can obstruct the urinary tract. While cystinuria has been reported in a number of breeds, it is particularly severe in Newfoundlands. Several mutations have been shown to cause the condition and the inheritance pattern varies between them. This variant is known to be inherited in an autosomal recessive fashion.

Clinical Overview
All clinical signs result from the failure to reabsorb certain amino acids and their subsequent precipitation in the urine. Dogs affected by cystinuria present with signs of recurring cystitis, hematuria, stranguria, and pollakiuria. The precipitation of amino acids in the urine results in the formation of crystals and calculi, leading to urolithiasis and urinary tract obstruction, in some cases.

Mutation Found In:
Landseer, Newfoundland

Gene Variant Tested
SLC3A1 Newfoundland

Clinical Signs
cystitis, hematuria, stranguria, urinary calculi, and urinary tract obstruction

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Brons, A.K., Henthorn, P.S., Raj, K., Fitzgerald, C.A., Liu, J., Sewell, A.C., Giger, U. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med 27:1400-8, 2013.

Osborne, CA, Sanderson, SL, Lulich, JP, Bartges, JW, Ulrich, LK, Koehler, LA, Bird, KA, Swanson, LL. Canine cystine urolithiasis. Cause, detection, treatment, and prevention. Vet Clin North Am Small Anim Pract. 1999 Jan;29(1):193-211, xiii.

39. Cystinuria Type II-A; mutation originally found in Australian Cattle Dog

Disease Category Type
renal

Description
Dogs with cystinuria are not able to reabsorb the amino acid cystine in their kidneys and therefore high concentrations can accumulate in the urinary tract causing formation of cystine crystals and stones that can obstruct the urinary tract. While cystinuria has been reported in a number of breeds, this variant is known to cause the condition in Australian Cattle Dogs. Several mutations have been shown to cause the condition and the inheritance pattern varies between them. This variant is known to be inherited in an autosomal dominant fashion.

Clinical Overview
All clinical signs result from the failure to reabsorb certain amino acids and their subsequent precipitation in the urine. Dogs affected by cystinuria present with signs of recurring cystitis, hematuria, stranguria, and pollakiuria. The precipitation of amino acids in the urine results in the formation of crystals and calculi, leading to urolithiasis and urinary tract obstruction, in some cases.

Mutation Found In:
Australian Cattle Dog, Australian Stumpy Tail Cattle Dog

Gene Variant Tested
SLC3A1 IIA

Clinical Signs
cystitis, hematuria, stranguria, urinary calculi, and urinary tract obstruction

Mode of Inheritance
autosomal dominant

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Casal ML, Giger U, Bovee KC, Patterson DF. Inheritance of cystinuria and renal defect in Newfoundlands. J Am Vet Med Assoc. 1995 Dec 15;207(12):1585-9.

Brons, A.K., Henthorn, P.S., Raj, K., Fitzgerald, C.A., Liu, J., Sewell, A.C., Giger, U. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med 27:1400-8, 2013.

40. Degenerative Myelopathy, (DM)

Disease Category Type
neurologic

Description
Degenerative myelopathy (DM) is an inherited neurologic disorder found in many dog breeds but most commonly associated with the German Shepherd Dog and Pembroke Welsh Corgi. It is not yet clear if all dogs carrying two copies of the mutation will develop clinical signs, especially considering the variable presentation noted among breeds found to carry it. DM is inherited in an autosomal recessive fashion. Dogs affected by DM show a slowly progressive loss of coordination that starts in the hind limbs and progresses forward, with the dog becoming increasingly more paretic. The clinical signs are related to the degeneration of the white matter of the spinal cord and generally result in euthanasia.

Clinical Overview
DM is a neurodegenerative disease of the spinal cord that is most commonly seen in adult German Shepherd Dogs but many other breeds have been reported to also be affected. Affected dogs first begin by exhibiting muscle wasting, proprioceptive deficits, and knuckling of the hind feet. Though the condition is not painful, affected dogs will eventually require assistance walking. As the condition progresses, it moves up the spinal cord and the dog's neurologic deficits mirror the progress, losing fecal and urinary continence and eventually involving the front legs and the brainstem. Euthanasia is usually elected.

Mutation Found In:
All Breeds

Gene Variant Tested
SOD1

Clinical Signs
proprioceptive deficits, knuckling hind feet, muscle wasting, paresis, incontinence

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Awano T, Johnson GS, Wade CM, Katz ML, Johnson GC, Taylor JF, Perloski M, Biagi T, Baranowska I, Long S, March PA, Olby NJ, Shelton GD, Khan S, O'Brien DP, Lindblad-Toh K, Coates JR. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2009 Feb 24; 106(8):2794-9.

Coates JR, March PA, Oglesbee M, Ruaux CG, Olby NJ, Berghaus RD, O'Brien DP, Keating JH, Johnson GS, Williams DA. Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. J Vet Intern Med. 2007 Nov-Dec; 21(6):1323-31.

Coates JR, Wininger FA. Canine degenerative myelopathy. Vet Clin North Am Small Anim Pract. 2010 Sep; 40(5):929-50.

Shelton GD, Johnson GC, O'Brien DP, Katz ML, Pesayco JP, Chang BJ, Mizisin AP, Coates JR. Degenerative myelopathy associated with a missense mutation in the superoxide dismutase 1 (SOD1) gene progresses to peripheral neuropathy in Pembroke Welsh Corgis and Boxers. J Neurol Sci. 2012 Jul 15;318(1-2):55-64.

Zeng R, Coates JR, Johnson GC, Hansen L, Awano T, Kolicheski A, Ivansson E, Perloski M, Lindblad-Toh K, O'Brien DP, Guo J, Katz ML, Johnson GS. Breed Distribution of SOD1 Alleles Previously Associated with Canine Degenerative Myelopathy. J Vet Intern Med. 2014 Feb 13.

41. Dental Hypomineralization; mutation originally found in Border Collie

Disease Category Type
dental

Description
Dental hypomineralization is a hereditary dental disease that is caused by abnormal mineralization of teeth during dental development. The disease causes abnormal tooth wear, pulpitis, and tooth loss. The disorder has been described in Border Collies. The genetic defect is estimated to be relatively common within the breed with approximately 11% of the breed population being carriers. The mode of inheritance is autosomal recessive.

Clinical Overview
The disorder causes brownish dental discoloration and abnormal wear of teeth. As the teeth wear, the biting surfaces of the teeth darkens, become dark brown in color; the enamel layer may also show a light brown discoloration and appear dull. The disorder causes severe tooth wear leading to pulp exposure, chronic inflammation of the pulp, and pulpal necrosis. Histologically, dentin of affected dogs has an abnormal structure and the enamel can be slightly hypoplastic. Affected dogs require regular dental treatment.

Mutation Found In:
Border Collie

Gene Variant Tested
FAM20C

Clinical Signs
abnormal tooth wear, pulpitis, teeth loss, severe tooth hypomineralization

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Hytönen M, Arumilli M, Lappalainen A, Owczarek-Lipska M, Jagannathan V, Hundi S, Salmela E, Venta P, Sarkiala E, Jokinen T, Gorgas D, Kere J, Nieminen P, Drögemüller C, Lohi H. Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes. PLOS Genetics. 2016 May 17;12(5):e1006037.

42. Dilated Cardiomyopathy, (DCM); mutation originally found in Standard Schnauzer

Disease Category Type
cardiac

Description
Dilated cardiomyopathy (DCM) is a cardiac disorder that is seen in many breeds. Typical clinical signs of this condition are caused by congestive heart failure. The genetic basis of this disease varies between breeds. The inheritance pattern of this mutation most closely resembles autosomal recessive and has been found in the Standard Schnauzer.

Clinical Overview
DCM is a cardiac disorder that results in an enlarged heart and thin heart muscle. These changes result in the heart’s diminished ability to serve as a pump, leading to cardiac failure. The clinical signs of cardiac failure are exercise intolerance, persistent cough, breathing difficulties, and swelling of the abdomen (ascites). DCM is also characterized by arrhythmias which can cause sudden cardiac death without any previous clinical signs.

Mutation Found In:
Standard Schnauzer

Gene Variant Tested
RBM20

Clinical Signs
cardiac enlargement, poor myocardial contractility, arrhythmia, congestive heart failure and sudden cardiac death

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gilliam DH. Molecular Genetic Studies of Canine Inherited Diseases Including SAMS, Neuronal Ceroid Lipofuscinosis and Dilated Cardiomyopathy. PhD dissertation. University of Missouri, 2016.

43. Dominant Progressive Retinal Atrophy, (DPRA)

Disease Category Type
ocular

Description
Dominant Progressive Retinal Atrophy (DPRA) is one form of progressive retinal atrophy (PRA) characterized by degeneration of retinal photoreceptors that result in blindness. DPRA is inherited in an autosomal dominant fashion and has been identified in Bullmastiffs and English Mastiffs. Affected dogs eventually develop blindness.

Clinical Overview
Progressive retinal atrophy (PRA) is an inherited eye disease in which retinal photoreceptors degenerate. The first clinical sign of the disease is reduced vision in the dark but eventually DPRA will result in blindness. Typically, signs of the disease occur at 6 to 18 months. The rate at which the disease progresses can vary but most affected dogs are blind by the age of 4 years.

Mutation Found In:
Bullmastiff, Mastiff

Gene Variant Tested
RHO

Clinical Signs
loss of vision and blindness

Mode of Inheritance
autosomal dominant

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kijas JW, Miller BJ, Pearce-Kelling SE, Aguirre GD, Acland GM. Canine models of ocular disease: outcross breedings define a dominant disorder present in the English mastiff and bull mastiff dog breeds. J Hered 94:27-30, 2003.

Kijas JW, Cideciyan AV, Aleman TS, Pianta MJ, Pearce-Kelling SE, Miller BJ, Jacobson SG, Aguirre GD, Acland GM. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc Nat Acad Sci U S A 99:6328-6333, 2002.

44. Duchenne or Dystrophin Muscular Dystrophy, (DMD); mutation originally found in Norfolk Terrier

Disease Category Type
muscular

Description
Dystrophin-deficient muscular dystrophy (Duchenne muscular dystrophy) is a progressive, hereditary disorder leading to muscular dysfunction. The disease is caused by the deficiency of dystrophin that protects muscles from damage during muscle contraction. The disease causes progressive muscle weakness, respiratory problems, and cardiomyopathy. The prognosis of the disease is grave. A form of the disease has been described in Norfolk terriers. The mode of inheritance is X-linked.

Clinical Overview
Clinical signs of the disease appear at a young age. Affected puppies show progressive muscular weakness, respiratory problems, and have cardiomyopathy. Glucocorticoid therapy and dantrolene therapy may provide temporary improvement. Affected dogs are euthanized as the disease reaches its terminal state. The disease is caused by the deficiency of a protein that is required for protection of muscle cells during muscle contraction.

Mutation Found In:
Norfolk Terrier

Gene Variant Tested
Dystrophin Norfolk

Clinical Signs
progressive muscular weakness, respiratory dysfunction, cardiomyopathy

Mode of Inheritance
X-linked

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Jenkins C, Forman O. Identification of a novel frameshift mutation in the DMD gene as the cause of muscular dystrophy in a Norfolk terrier dog. Canine Genetics and Epidemiology;2:7, 2015.

45. Dystrophic Epidermolysis Bullosa; mutation originally found in Central Asian Ovcharka

Disease Category Type
dermal

Description
Dystrophic epidermolysis bullosa is a skin disorder; this variant has been found to cause the condition in the Central Asian Ovcharka. Affected dogs suffer from blistering of the skin and lesions in the oral cavity and upper digestive tract; clinical signs may diminish around 8 months of age. The condition is characterized by a dysfunctional collagen protein that causes intradermal separation of the epidermis from the underlying dermis. Dystrophic epidermolysis bullosa is inherited in an autosomal recessive manner.

Clinical Overview
Dystrophic epidermolysis bullosa (DEB) results in fragile skin casued by the dysfunctional collagen protein. Therefore, areas of high friction such as footpads, groin, and oral cavity tend to exhibit the characteristics blisters. Puppies may be smaller than littermates, likely as a result of eating less due to the discomfort this poses.

Mutation Found In:
Central Asian Ovcharka

Gene Variant Tested
COL7A1 Central Asian Ovcharka

Clinical Signs
blistering of the skin, lesions in oral cavity and upper digestive tract, and growth retardation

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Baldeschi C, Gache Y, Rattenholl A, Bouillé P, Danos O, Ortonne JP, Bruckner-Tuderman L, Meneguzzi G. Genetic correction of canine dystrophic epidermolysis bullosa mediated by retroviral vectors. Hum Mol Genet. 1;12(15):1897-1905, 2003.

Palazzi X, Marchal T, Chabanne L, Spadafora A, Magnol JP, Meneguzzi G. Inherited dystrophic epidermolysis bullosa in inbred dogs: A spontaneous animal model for somatic gene therapy. J Invest Dermatol. 115(1):135-137, 2000.

46. Dystrophic Epidermolysis Bullosa; mutation originally found in Golden Retriever

Disease Category Type
dermal

Description
Dystrophic epidermolysis bullosa is a skin disorder affecting Golden Retrievers. Affected dogs suffer from blistering of the skin and lesions in the oral cavity and upper digestive tract; clinical signs may diminish around 8 months of age. The condition is characterized by a dysfunctional collagen protein that causes intradermal separation of the epidermis from the underlying dermis. Dystrophic epidermolysis bullosa is inherited in an autosomal recessive manner.

Clinical Overview
Dystrophic epidermolysis bullosa (DEB) results in fragile skin casued by the dysfunctional collagen protein. Therefore, areas of high friction such as footpads, groin, and oral cavity tend to exhibit the characteristics blisters. Puppies may be smaller than littermates, likely as a result of eating less due to the discomfort this poses.

Mutation Found In:
Golden Retriever

Gene Variant Tested
COL7A1 Golden Retriever

Clinical Signs
blistering of the skin, lesions in oral cavity and upper digestive tract, and growth retardation

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Baldeschi C, Gache Y, Rattenholl A, Bouillé P, Danos O, Ortonne JP, Bruckner-Tuderman L, Meneguzzi G. Genetic correction of canine dystrophic epidermolysis bullosa mediated by retroviral vectors. Hum Mol Genet. 1;12(15):1897-1905, 2003.

Palazzi X, Marchal T, Chabanne L, Spadafora A, Magnol JP, Meneguzzi G. Inherited dystrophic epidermolysis bullosa in inbred dogs: A spontaneous animal model for somatic gene therapy. J Invest Dermatol. 115(1):135-137, 2000.

47. Early-Onset Progressive Polyneuropathy; mutation originally found in Alaskan Malamute

Disease Category Type
neuromuscular

Description
Alaskan Malamutes suffer from early-onset progressive polyneuropathy which is characterized by the dysfunction and atrophy of multiple nerve types. The disorder is inherited in an autosomal recessive manner and will eventually lead to tetraparesis.

Clinical Overview
Early-onset polyneuropathy is characterized by progressive neuronal degeneration of peripheral nerves. First observable signs in Alaskan Malamutes are voice changes, inspiratory stridor, and pelvic limb weakness with progression to muscle weakness of all four limbs, muscle atrophy, and exercise intolerance. Affected dogs are usually reluctant to stand still and climb stairs. Dogs suffering from early-onset progressive polyneuropathy have decreased spinal reflexes in all four limbs. The onset of clinical signs is 3-19 months of age in Alaskan Malamutes. Early-onset polyneuropathy is a progressive condition leading to tetraparesis.

Mutation Found In:
Alaskan Malamute

Gene Variant Tested
NDRG1 Alaskan Malamute

Clinical Signs
walking difficulties, exercise intolerance, voice changes, progressive severe muscle atrophy, ataxia, and paralysis of larynx and extremities

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Drogemuller C, Becker D, Kessler B, Kemter E, Tetens J, Jurina K, Jaderlund KH, Flagstad A, Perloski M, Lindblad-Toh K, Matiasek K. A deletion in the N-myc downstream regulated gene 1 (NDRG1) gene in Greyhounds with polyneuropathy. PLoS One 5:e11258, 2010.

Bruun CS, Jäderlund KH, Berendt M, Jensen KB, Spodsberg EH, Gredal H, Shelton GD, Mickelson JR, Minor KM, Lohi H, Bjerk's I, Stigen O, Espenes A, Rohdin C, Edlund R, Ohlsson J, Cizinauskas S, Leifsson PS, Drögemüller C, Moe L, Cirera S, Fredholm M. A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy. PLoS One 8(2):e54547, 2013.

Rentmeister K, Bilzer T, Petri S., Schanen G, Fehr M, Distl O, Tipold A. Hereditary polyneuropathy in the Alaskan Malamute. Tierärztl Prax 2012;40:26-34.

48. Epidermolytic Hyperkeratosis

Disease Category Type
dermal

Description
Epidermolytic hyperkeratosis is a congenital ichthyotic skin disorder affecting Norfolk Terriers. Clinical signs include fragile skin, hyperkeratosis, and hyperpigmentation. Epidermolytic hyperkeratosis is inherited in an autosomal recessive manner.

Clinical Overview
Affected dogs suffer from fragile skin, hyperkeratosis (thickening of the skin), and hyperpigmentation (darkening of the skin). Mechanical trauma can cause sloughing, erosion, and ulceration of the fragile skin. Sloughing of the skin can be observed in puppies only a few days old. Hyperpigmentation and hyperkeratosis are present in adulthood. Footpads, hair, teeth, and claws are unaffected.

Mutation Found In:
Norfolk Terrier

Gene Variant Tested
KRT10

Clinical Signs
fragile skin, hyperkeratosis, and hyperpigmentation

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Credille KM, Barnhart KF, Minor JS, Dunstan RW. Mild recessive epidermolytic hyperkeratosis associated with a novel keratin 10 donor splice-site mutation in a family of Norfolk terrier dogs. Br J Dermatol. 153(1):51-58, 2005.

49. Episodic Falling Syndrome, (EFS)

Disease Category Type
neuromuscular

Description
Episodic falling syndrome (EFS) is a condition causing the temporary inability to relax muscles. EFS is characterized by increased muscle tone and muscle spasticity in all four limbs resulting in collapse episodes which are usually a few seconds to several minutes long. The episodes are often associated with exercise, excitement, or stress. Episodic falling syndrome is encountered in the Cavalier King Charles Spaniel and the disorder is inherited in an autosomal recessive manner.

Clinical Overview
First signs of EFS can be seen in dogs 3-7 months of age. Episodic collapses are often associated with exercise, excitement, or stressful events. Episodes are usually a few seconds to several minutes in length and resolve on their own. Episodic collapses begin with increased muscle tone leading to temporary immobility of the dog. The affected dog usually falls down with its limbs in an extended position. During an episode, an affected dog may exhibit bunny hop-like movements, have its back arched, and vocalize. The dog experiencing an episode stays fully conscious throughout. The severity and number of episodes vary over the course of the dog's life. Affected dogs appear neurologically normal between episodes.

Mutation Found In:
Cavalier King Charles Spaniel, English Toy Spaniel, King Charles Spaniel

Gene Variant Tested
BCAN

Clinical Signs
increased muscle tone, spasticity, and collapses

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Forman OP, Penderis J, Hartley C, Hayward LJ, Ricketts SL, Mellersh CS Parallel mapping and simultaneous sequencing reveals deletions in BCAN and FAM83H associated with discrete inherited disorders in a domestic dog breed. PLoS Genet 8(1):e1002462, 2012.

Gill JL, Tsai KL, Krey C, Noorai RE, Vanbellinghen J-F, Garosi LS, Shelton GD, Clark LA, Harvey RJ. A canine BCAN microdeletion associated with Episodic Falling Syndrome. Neurobiol Dis 45(1):130-136, 2012.

Garosi LS, Platt SR, Shelton GD. Hypertonicity in Cavalier King Charles Spaniels. J Vet Intern Med 2002; 16:330.

50. Exercise-Induced Collapse, (EIC)

Disease Category Type
neuromuscular

Description
Exercise-induced collapse (EIC) is an inherited neuromuscular disorder first identified in Labrador Retrievers, which presents as exercise intolerance in otherwise normal dogs. Affected dogs appear normal during low to moderately strenuous activity, but they develop a wobbly, uncoordinated gait that is most severe in the hind limbs after brief bouts of strenuous activity. EIC is inherited in an autosomal recessive manner.

Clinical Overview
EIC is caused by a mutation in the DNM1 gene that has been identified in the Labrador Retriever. Affected dogs appear normal during low to moderately strenuous activity, but they develop a wobbly, uncoordinated gait that is most severe in the hind limbs after brief bouts of strenuous activity. Typically the dogs remain conscious and are not in pain during an episode. In some cases, however, the signs are severe with full body weakness and low muscle tone (flaccid paralysis), confusion, loss of consciousness, and seizures. Very rarely, death can occur. The episodes typically last 5-10 minutes and most dogs will recover completely within 15-30 minutes.

Mutation Found In:
American Cocker Spaniel, Boykin Spaniel, Bouvier des Flandres, Chesapeake Bay Retriever, Clumber Spaniel, Curly Coated Retriever, German Wirehaired Pointer, Labrador Retriever, Mixed breed, Old English Sheepdog, Welsh Corgi Pembroke

Gene Variant Tested
DNM1

Clinical Signs
hind limb weakness and ataxia after intense exercise and in severe cases short-term, flaccid paralysis

Mode of Inheritance
autosomal recessive

Disease Severity
mild to moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Furrow E, Minor KM, Taylor SM, Mickelson JR, Patterson EE. Relationship between dynamin 1 mutation status and characteristics of recurrent episodes of exercise-induced collapse in Labrador Retrievers. J Am Vet Med Assoc. 2013 Mar 15;242(6):786-91.

Minor KM, Patterson EE, Keating MK, Gross SD, Ekenstedt KJ, Taylor SM, Mickelson JR. Presence and impact of the exercise-induced collapse associated DNM1 mutation in Labrador retrievers and other breeds. Vet J. 2011 Aug; 189(2):214-9.

Taylor SM, Shmon CL, Adams VJ, Mickelson JR, Patterson EN, Shelton GD. Evaluations of labrador retrievers with exercise-induced collapse, including response to a standardized strenuous exercise protocol. J Am Anim Hosp Assoc. 2009 Jan-Feb; 45(1):3-13.

Patterson EE, Minor KM, Tchernatynskaia AV, Taylor SM, Shelton GD, Ekenstedt KJ, Mickelson JR. A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse. Nat Genet. 2008 Oct; 40(10):1235-9.

Taylor SM, Shmon CL, Shelton GD, Patterson EN, Minor K, Mickelson JR. Exercise-induced collapse of Labrador retrievers: survey results and preliminary investigation of heritability. J Am Anim Hosp Assoc. 2008 Nov-Dec: 44(6):295-301.

51. Factor IX Deficiency or Hemophilia B; mutation Gly379Glu

Disease Category Type
blood

Description
Hemophilia B is a blood disorder encountered in several breeds and is related to a factor IX deficiency. The disease follows an X-linked mode of inheritance. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor IX is one of the proteins necessary for blood coagulation and its deficiency causes hemophilia B in an affected dog. Hemophilia B is a milder blood disorder than hemophilia A, but it may still cause life-threatening bleeding. Excessive and prolonged bleeding may be observed during tooth extractions, routine surgeries, and even minor traumas. The condition is usually more severe for active dogs of large size.

Mutation Found In:
Unknown

Gene Variant Tested
FIX G1477A

Clinical Signs
excessive or life threatening bleeding

Mode of Inheritance
X-linked

Disease Severity
moderate discomfort

References: Online Database

References: Scientific Articles
Brooks MB, Gu W, Barnas JL, Ray J, Ray K. A Line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs. Mamm Genome 14(11):788-95, 2003.

Gu W, Brooks M, Catalfamo J, Ray J, Ray K. Two distinct mutations cause severe hemophilia B in two unrelated canine pedigrees. Thromb Haemost 82(4):1270-5, 1999.

Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA. Canine Hemophilia-B Resulting from a Point Mutation with Unusual Consequences. Proc Natl Acad Sci USA 86:10095-10099, 1989.

Mauser AE, Whitlark J, Whitney KM, Lothrop CD. A Deletion Mutation Causes Hemophilia B In Lhasa Apso Dogs. Blood 88: 3451-3455, 1996.

Mischke R, Kuhnlein P, Kehl A, Langbein-Detsch I, Steudle F, Schmid A, Dandekar T, Czwalinna A, Muller E. G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Vet J 187(1):113-8, 2011.

52. Factor IX Deficiency or Hemophilia B; mutation originally found in Airedale Terrier

Disease Category Type
blood

Description
Hemophilia B is a blood disorder encountered in several breeds and is related to a factor IX deficiency. The disease follows an X-linked mode of inheritance. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor IX is one of the proteins necessary for blood coagulation and its deficiency causes hemophilia B in an affected dog. Hemophilia B is a milder blood disorder than hemophilia A, but it may still cause life-threatening bleeding. Excessive and prolonged bleeding may be observed during tooth extractions, routine surgeries, and even minor traumas. The condition is usually more severe for active dogs of large size.

Mutation Found In:
Airedale Terrier

Gene Variant Tested
FIX Airedale Terrier

Clinical Signs
excessive or life threatening bleeding

Mode of Inheritance
X-linked

Disease Severity
moderate discomfort

References: Online Database

References: Scientific Articles
Brooks MB, Gu W, Barnas JL, Ray J, Ray K. A Line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs. Mamm Genome 14(11):788-95, 2003.

Gu W, Brooks M, Catalfamo J, Ray J, Ray K. Two distinct mutations cause severe hemophilia B in two unrelated canine pedigrees. Thromb Haemost 82(4):1270-5, 1999.

Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA. Canine Hemophilia-B Resulting from a Point Mutation with Unusual Consequences. Proc Natl Acad Sci USA 86:10095-10099, 1989.

Mauser AE, Whitlark J, Whitney KM, Lothrop CD. A Deletion Mutation Causes Hemophilia B In Lhasa Apso Dogs. Blood 88: 3451-3455, 1996.

Mischke R, Kuhnlein P, Kehl A, Langbein-Detsch I, Steudle F, Schmid A, Dandekar T, Czwalinna A, Muller E. G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Vet J 187(1):113-8, 2011.

53. Factor IX Deficiency or Hemophilia B; mutation originally found in Lhasa Apso

Disease Category Type
blood

Description
Hemophilia B is a blood disorder encountered in several breeds and is related to a factor IX deficiency. The disease follows an X-linked mode of inheritance. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor IX is one of the proteins necessary for blood coagulation and its deficiency causes hemophilia B in an affected dog. Hemophilia B is a milder blood disorder than hemophilia A, but it may still cause life-threatening bleeding. Excessive and prolonged bleeding may be observed during tooth extractions, routine surgeries, and even minor traumas. The condition is usually more severe for active dogs of large size.

Mutation Found In:
Lhasa Apso

Gene Variant Tested
FIX Lhasa Apso

Clinical Signs
excessive or life threatening bleeding

Mode of Inheritance
X-linked

Disease Severity
moderate discomfort

References: Online Database

References: Scientific Articles
Brooks MB, Gu W, Barnas JL, Ray J, Ray K. A Line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs. Mamm Genome 14(11):788-95, 2003.

Gu W, Brooks M, Catalfamo J, Ray J, Ray K. Two distinct mutations cause severe hemophilia B in two unrelated canine pedigrees. Thromb Haemost 82(4):1270-5, 1999.

Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA. Canine Hemophilia-B Resulting from a Point Mutation with Unusual Consequences. Proc Natl Acad Sci USA 86:10095-10099, 1989.

Mauser AE, Whitlark J, Whitney KM, Lothrop CD. A Deletion Mutation Causes Hemophilia B In Lhasa Apso Dogs. Blood 88: 3451-3455, 1996.

Mischke R, Kuhnlein P, Kehl A, Langbein-Detsch I, Steudle F, Schmid A, Dandekar T, Czwalinna A, Muller E. G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Vet J 187(1):113-8, 2011.

54. Factor VII Deficiency

Disease Category Type
blood

Description
Factor VII deficiency is an inherited bleeding disorder encountered in several breeds. The related clinical signs are typically mild but may vary in severity, and excessive bleeding only occurs after a severe trauma or surgery. The mode of inheritance for this mutation is autosomal recessive.

Clinical Overview
Blood coagulation is a complex process. FVII is a vitamin K-dependent clotting factor that, when activated, plays a significant role in the initiation of coagulation. A genetic deficiency of this protein leads to a tendency for excessive bleeding. Clinical signs are typically mild and excessive bleeding occurs only after severe trauma or surgery. However, the severity of the disorder may vary from one patient to another.

Mutation Found In:
Airedale Terrier, Alaskan Klee Kai, Beagle, Finnish Hound, Giant Schnauzer, Scottish Deerhound, Welsh Springer Spaniel

Gene Variant Tested
F7

Clinical Signs
excessive bleeding

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kaae JA, Callan MB, Brooks MB. Hereditary factor VII deficiency in the Alaskan Klee Kai dog. J Vet Intern Med 21(5):976-81, 2007.

Callan MB, Aljamali MN, Margaritis P, Griot-Wenk ME, Pollak ES, Werner P, Giger U, High KA. A novel missense mutation responsible for factor VII deficiency in research Beagle colonies. J Thromb Haemost 4: 2616-22, 2006.

55. Factor VIII Deficiency or Hemophilia A; mutation originally found in Boxer

Disease Category Type
blood

Description
Hemophilia A is an inherited bleeding disorder encountered in several breeds. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs. The disease follows an X-linked mode of inheritance and is therefore more commonly observed in male dogs. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor VIII is one of the proteins necessary for the blood coagulation process and a deficiency of this protein causes hemophilia A in an affected dog. Clinical signs of hemophilia A vary depending on the activity of factor VIII in the blood. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. Exceptionally excessive and prolonged bleeding may be observed during shedding of deciduous teeth, routine surgeries, and even minor traumas. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs.

Mutation Found In:
Boxer

Gene Variant Tested
FVIII Boxer

Clinical Signs
potentially life threatening bleeding diathesis, hematomas, or abdominal bleeding

Mode of Inheritance
X-linked

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wilhelm C, Czwalinna A, Hoffmann M, Mischke R, Ganser A, Von Depka M. A mutation leading to a stop codon in the FVIII gene is the cause of severe canine Hemophilia A. J Thromb Haemost 1 Sup P0672, 2013.

56. Factor VIII Deficiency or Hemophilia A; mutation originally found in German Shepherd Dog

Disease Category Type
blood

Description
Hemophilia A is an inherited bleeding disorder encountered in several breeds. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs. The disease follows an X-linked mode of inheritance and is therefore more commonly observed in male dogs. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor VIII is one of the proteins necessary for the blood coagulation process and a deficiency of this protein causes hemophilia A in an affected dog. Clinical signs of hemophilia A vary depending on the activity of factor VIII in the blood. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. Exceptionally excessive and prolonged bleeding may be observed during shedding of deciduous teeth, routine surgeries, and even minor traumas. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs.

Mutation Found In:
German Shepherd Dog

Gene Variant Tested
FVIII

Clinical Signs
potentially life threatening bleeding diathesis, hematomas, or abdominal bleeding

Mode of Inheritance
X-linked

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wilhelm C, Czwalinna A, Hoffmann M, Mischke R, Ganser A, Von Depka M. A mutation leading to a stop codon in the FVIII gene is the cause of severe canine Hemophilia A. J Thromb Haemost 1 Sup P0672, 2013.

57. Factor VIII Deficiency or Hemophilia A; mutation originally found in Havanese

Disease Category Type
blood

Description
Hemophilia A is an inherited bleeding disorder encountered in several breeds. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs. The disease follows an X-linked mode of inheritance and is therefore more commonly observed in male dogs. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor VIII is one of the proteins necessary for the blood coagulation process and a deficiency of this protein causes hemophilia A in an affected dog. Clinical signs of hemophilia A vary depending on the activity of factor VIII in the blood. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. Exceptionally excessive and prolonged bleeding may be observed during shedding of deciduous teeth, routine surgeries, and even minor traumas. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs.

Mutation Found In:
Havanese

Gene Variant Tested
FVIII Havanese

Clinical Signs
potentially life threatening bleeding diathesis, hematomas, or abdominal bleeding

Mode of Inheritance
X-linked

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wilhelm C, Czwalinna A, Hoffmann M, Mischke R, Ganser A, Von Depka M. A mutation leading to a stop codon in the FVIII gene is the cause of severe canine Hemophilia A. J Thromb Haemost 1 Sup P0672, 2013.

58. Factor VIII Deficiency or Hemophilia A; mutation originally found in Old English Sheepdog

Disease Category Type
blood

Description
Hemophilia A is an inherited bleeding disorder encountered in several breeds. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs. The disease follows an X-linked mode of inheritance. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor VIII is one of the proteins necessary for the blood coagulation process and a deficiency of this protein causes hemophilia A in an affected dog. Clinical signs of hemophilia A vary depending on the activity of factor VIII in the blood. Hematomas or abdominal bleeding may be observed to occur with no underlying reason in a severely affected dog. Exceptionally excessive and prolonged bleeding may be observed during shedding of deciduous teeth, routine surgeries, and even minor traumas. If untreated, the disorder can lead to death caused by blood loss. The condition is usually more severe in large, active dogs.

Mutation Found In:
Old English Sheepdog

Gene Variant Tested
FVIII

Clinical Signs
potentially life threatening bleeding diathesis, hematomas, or abdominal bleeding

Mode of Inheritance
X-linked

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wilhelm C, Czwalinna A, Hoffmann M, Mischke R, Ganser A, Von Depka M. A mutation leading to a stop codon in the FVIII gene is the cause of severe canine Hemophilia A. J Thromb Haemost 1 Sup P0672, 2013.

Lozier J, Kloos M, Merricks E, Lemoine N, Whitford M, Raymer R, Bellinger D, Nichols T.Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII. Comp Med. 2016;66(5):405-411.

59. Factor VIII Deficiency or Hemophilia A; p.Cys548Tyr mutation originally found in German Shepherd Dog

Disease Category Type
blood

Description
Hemophilia A is an inherited bleeding disorder encountered in several breeds. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs. The disease follows an X-linked mode of inheritance and is therefore more commonly observed in male dogs. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Blood coagulation is a complex process. Factor VIII is one of the proteins necessary for the blood coagulation process and a deficiency of this protein causes hemophilia A in an affected dog. Clinical signs of hemophilia A vary depending on the activity of factor VIII in the blood. Hematomas or abdominal bleeding without apparent reason may be observed in a severely affected dog. Exceptionally excessive and prolonged bleeding may be observed during shedding of deciduous teeth, routine surgeries, and even minor traumas. If untreated, the disorder can lead to death caused by bleeding. The condition is usually more severe in large, active dogs.

Mutation Found In:
German Shepherd Dog

Gene Variant Tested
FVIII German Shepherd Dog

Clinical Signs
potentially life threatening bleeding diathesis, hematomas, or abdominal bleeding

Mode of Inheritance
X-linked

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wilhelm C, Czwalinna A, Hoffmann M, Mischke R, Ganser A, Von Depka M. A mutation leading to a stop codon in the FVIII gene is the cause of severe canine Hemophilia A. J Thromb Haemost 1 Sup P0672, 2013.

60. Factor XI Deficiency

Disease Category Type
blood

Description
Factor XI deficiency is a hereditary disorder that impacts blood coagulation. Many affected dogs remain asymptomatic. The disease usually causes a mild, spontaneous bleeding disorder but more severe bleeding may occur following surgery. Therapy is limited to supportive care (which can include transfusions if needed) and avoiding surgery. The disorder affects the Kerry Blue Terrier breed. It has also been found in some lines of the Great Pyrenees and English Springer Spaniels. The mode of inheritance is autosomal dominant with incomplete penetrance.

Clinical Overview
The disorder is caused by the deficiency of the intrinsic clotting factor XI which leads to abnormally slow clot formation at the site of vascular injury. In most cases, the disorder causes mild, spontaneous bleeding which may presents as hematuria (blood in the urine), gingival bleeding, or epistaxis (bleeding from the nose). Many affected dogs may also remain asymptomatic. The disorder can sometimes cause severe, life-threatening bleeding 12 to 24 hours after surgical intervention. Excessive bleeding may also occur after trauma.

Mutation Found In:
Kerry Blue Terrier

Gene Variant Tested
FXI

Clinical Signs
bloody urine, gingival bleeding, nose bleed, severe bleeding after surgery or trauma

Mode of Inheritance
autosomal dominant

Signs Seen in Affected Carriers
delayed clotting

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Tcherneva E, Giger U. Molecular base of coagulation Factor XI deficiency in Kerry blue terrier. Bulg. J. Vet. Med., 10, No 4, 247?255, 2007.

61. Fanconi Syndrome

Disease Category Type
renal

Description
Fanconi syndrome is a condition of the renal tubules where the reabsorption capacity of the proximal renal tubules of the kidneys is impaired. This leads to excessive loss of essential metabolites such as glucose, electrolytes, amino acids, and proteins in the urine. Clinical signs of the disease include frequent drinking and urinating, weight loss, and poor hair coat. There are both acquired and inherited forms of Fanconi syndrome. An inherited form of the disease has been found in the Basenji.

Clinical Overview
Clinical signs typically include polyuria and polydipsia (increased amount and frequency of urination and drinking), muscle wasting, weight loss, metabolic acidosis, and poor coat quality. In dogs with Fanconi syndrome, urinalysis findings frequently identify the presence of glucose despite normal serum glucose levels. If left untreated, the disease leads to death secondary to renal failure. The onset of clinical signs typically varies between 4 and 7 years of age. The disease is caused by the impaired reabsorption capacity of the proximal renal tubules leading to urinary leakage of essential metabolites such as glucose, electrolytes, amino acids, and proteins. It has been speculated that low-level amounts of heavy metals could speed up kidney damage in affected dogs. This would explain the varying age of onset. Among Basenjis, the prevalence of the disease has been estimated to be about 10%.

Mutation Found In:
Basenji

Gene Variant Tested
FAN1 Basenji

Clinical Signs
increased drinking and urinating, glucosuria, weight loss, poor coat quality

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Farias FHG. Molecular genetic studies of canine inherited diseases. PhD dissertation. University of Missouri, 2011.

62. Fetal Onset Neuroaxonal Dystrophy, (FNAD)

Disease Category Type
neurologic

Description
Dogs with fetal onset neuroaxonal dystrophy (FNAD) die upon birth due to respiratory failure. The mutation was discovered in a laboratory colony of mixed breed dogs that were the outcome of breeding between a Giant Schnauzer and Beagle. The prevalence of FNAD in natural populations remains to be determined. Fetal onset neuroaxonal dystrophy is inherited as an autosomal recessive trait.

Clinical Overview
Fetal onset neuroaxonal dystrophy (FNAD) is a disorder that disturbs the development of motor neurons in the central nervous system. Scoliosis (abnormal lateral curvature of the spine) and multiple contracted joints (arthrogryposis) are often observed. Arthrogryposis causes affected puppies to have no voluntary movement of limbs. Respiratory deficiencies cause affected puppies to die at birth. Post-mortem examinations usually reveal abnormal swollen axons throughout the brain stem, spinal cord, and peripheral nerves.

Mutation Found In:
Giant Schnauzer, Laboratory colony of mixed breed dogs

Gene Variant Tested
MFN2

Clinical Signs
respiratory failure; arthrogryposis; scoliosis; hypoplasia of lungs, brain, and spine; and death upon birth

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Fyfe JC, Al-Tamimi RA, Liu J, Schäffer AA, Agarwala R, Henthorn PS. A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy. Neurogenetics 12:223-32, 2011.

Fyfe JC, Al-Tamimi RA, Castellani RJ, Rosenstein D, Goldowitz D, Henthorn PS. Inherited neuroaxonal dystrophy in dogs causing lethal, fetal-onset motor system dysfunction and cerebellar hypoplasia. J Comp Neurol 518:3771-84, 2010.

63. Focal Non-Epidermolytic Palmoplantar Keratoderma, (FNEPPK); mutation originally found in Dogue de Bordeaux

Disease Category Type
dermal

Description
Hereditary footpad hyperkeratosis (HFH) is a congenital skin disorder encountered in several breeds – this variant was found to be the causal mutation in the Dogue de Bordeaux and goes by the name focal non-epidermolytic palmoplantar keratoderma (FNEPPK). The disorder is characterized by hard, thickened, and cracked footpads. Unlike a similar condition in other breeds, FNEPPK affected dogs have a normal coat. FNEPPK is inherited in an autosomal recessive manner.

Clinical Overview
Focal non-epidermolytic palmoplantar keratoderma is a progressive condition characterized by dry and thickened footpads. The clinical signs include painful cracks and fissures on the footpads that may lead to secondary infections and lameness. Horny protrusions can be observed on all footpads. Affected dogs often avoid walking on rough surfaces. The clinical signs result from abnormal keratinous proliferation of cells of the skin. However, affected dogs do not exhibit epidermolytic changes and thus have normal nails and lack other cutaneous lesions. Typical onset of clinical signs occurs between 10 weeks and 1 year of age. Dogs suffering from FNEPPK have a normal lifespan if the footpads and nails are cared for appropriately.

Mutation Found In:
Dogue de Bordeaux

Gene Variant Tested
KRT16

Clinical Signs
hard and cracked footpads, severe keratinous proliferations along pawpads (horny protrusions)

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Scientific Articles
Plassais J, Guaguère E, Lagoutte L, Guillory AS, de Citres CD, Degorce-Rubiales F, Delverdier M, Vaysse A, Quignon P, Bleuart C, Hitte C, Fautrel A, Kaerle C, Bellaud P, Bensignor E, Queney G, Bourrat E, Thomas A, André C. A spontaneous KRT16 mutation in a dog breed: a model for human focal non-epidermolytic palmoplantar keratoderma (FNEPPK). J Invest Dermatol. 2015 Apr;135(4):1187-90.

64. Generalized Progressive Retinal Atrophy

Disease Category Type
ocular

Description
Progressive retinal atrophy (PRA) is an eye disorder encountered in several dog breeds. PRA is characterized by retinal degeneration and progressive loss of vision leading eventually to blindness. Many of the causative mutations behind different forms of PRA have been identified, but some have not. The mutation in the Schapendoes Dog causes a form of generalized PRA (gPRA) that has an autosomal recessive pattern of inheritance

Clinical Overview
Generalized PRA is a late onset, slowly progressing eye disorder. The first sign of the disease is night blindness as a result of degeneration of reticular rod cells. Later cone cells also start to degenerate, impairing day vision. The first signs appear typically at the age of 2 to 5 years, and result in blindness over the course of the next two to three years.

Mutation Found In:
Schapendoes Dog

Gene Variant Tested
CCDC66

Clinical Signs
night blindness and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Dekomien G, Vollrath C, Petrasch-Parwez E, Boevé MH, Akkad DA, Gerding WM, Epplen JT. Progressive retinal atrophy in Schapendoes dogs: mutation of the newly identified CCDC66 gene. Neurogenetics 11(2):163-174, 2010.

Lippmann T, Jonkisz A, Dobosz T, Petrasch-Parwez E, Epplen JT, Dekomien G. Haplotype-defined linkage region for gPRA in Schapendoes dogs. Mol Vis 7;13:174-180, 2007.

65. Glanzmann Thrombasthenia Type I, (GT); mutation originally found in Great Pyrenees

Disease Category Type
blood

Description
Glanzmann thrombasthenia (GT) type I is a blood disorder described in the Great Pyrenees and the Otterhound; this variant is known to cause the condition in the Great Pyrenees. GT is characterized by poor blood platelet aggregation leading to bleeding issues. The mode of inheritance is autosomal recessive.

Clinical Overview
Glanzmann thrombasthenia causes susceptibility to bleeding due to poor blood platelet aggregation. This is caused by a deficiency in a platelet membrane glycoprotein. Typical clinical signs include mucosal bleeding, such as nose bleeding, bleeding from the gums, intestinal bleeding, as well as blood in the urine. Abdominal blood spots under the skin or blood spots in the mouth may also be observed. More severe, prolonged bleeding may occur due to a trauma or surgery.

Mutation Found In:
Great Pyrenees

Gene Variant Tested
ITGA2B Great Pyrenees

Clinical Signs
nose bleeding, bleeding from the gums, and prolonged bleeding during trauma or surgery

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Lipscomb DL, Bourne C, Boudreaux MK. Two genetic defects in alphaIIb are associated with type I Glanzmann's thrombasthenia in a Great Pyrenees dog: a 14-base insertion in exon 13 and a splicing defect of intron 13. Vet Pathol 37(6):581-588, 2000.

Boudreaux MK, Catalfamo JL. Molecular and genetic basis for thrombasthenic thrombopathia in Otterhounds. Am J Vet Res 62(11):1797-1804, 2001.

66. Glanzmann Thrombasthenia Type I, (GT); mutation originally found in mixed breed dogs

Disease Category Type
blood

Description
Glanzmann thrombasthenia (GT) type I is a hereditary bleeding disorder. Genetic causes for the disease have been identified in the Great Pyrenees, the Otterhound, and in mixed breed dogs. GT is characterized by poor blood platelet aggregation leading to bleeding issues. The mode of inheritance is autosomal recessive.

Clinical Overview
Glanzmann thrombasthenia causes susceptibility to bleeding due to poor blood platelet aggregation. This is caused by a deficiency in a platelet membrane glycoprotein. Typical clinical signs include mucosal bleeding, such as nose bleeding, bleeding from the gums, and intestinal bleeding, as well as blood in the urine. Abdominal blood spots under the skin or blood spots in the mouth may also be observed. More severe, prolonged bleeding may occur due to a trauma or surgery.

Mutation Found In:
Mixed breed

Gene Variant Tested
ITGA2B mixed breed

Clinical Signs
nose bleeding, bleeding from the gums, and prolonged bleeding during trauma or surgery

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Lipscomb DL, Bourne C, Boudreaux MK. Two genetic defects in alphaIIb are associated with type I Glanzmann's thrombasthenia in a Great Pyrenees dog: a 14-base insertion in exon 13 and a splicing defect of intron 13. Vet Pathol 37(6):581-588, 2000.

Boudreaux MK, Catalfamo JL. Molecular and genetic basis for thrombasthenic thrombopathia in Otterhounds. Am J Vet Res 62(11):1797-1804, 2001.

Haysom LZ, Kennerly RM, Müller RD, Smith‐Carr S, Christopherson PW, Boudreaux MK. Identification and Characterization of Glanzmann Thrombasthenia in 2 Closely Related Mixed‐breed Dogs. J Vet Intern Med. 2016 Mar-Apr; 30(2): 642–646. doi: 10.1111/jvim.13825

67. Globoid Cell Leukodystrophy or Krabbe Disease, (GLD); mutation originally found in Irish Setter

Disease Category Type
neuromuscular

Description
Globoid cell leukodystrophy is a neurologic lysosomal storage disease that causes severe neuronal degeneration. The underlying cause of the disorder is a deficiency of a lysosomal galactocerebrosidase enzyme. This enzyme deficiency causes defects in the production of myelin that protects and insulates neurons. This particular genetic variant has been found to cause GLD in Irish Setters. Globoid cell leukodystrophy is an autosomal recessive disorder.

Clinical Overview
GLD is characterized by muscle weakness, tremors, and ataxia (uncoordinated movement). Clinical signs of the disease also include behavioral changes, incoherence, blindness, and deficits in normal reflexes. GLD is a progressive condition in which the characteristic signs of the disease are first observed in the hind legs. The first signs of the disease can be seen in dogs 1-5 months of age. Affected dogs do not survive to adulthood and they are usually euthanized before 9 months of age.

Mutation Found In:
Irish Setter

Gene Variant Tested
GALC setters

Clinical Signs
muscle weakness, ataxia, tremor, paralysis, and behavioral changes

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
McGraw RA, Carmichael KP. Molecular basis of globoid cell leukodystrophy in Irish setters. Vet J 171:370-2, 2006.

Wenger DA, Victoria T, Rafi MA, Luzi P, Vanier MT, Vite C, Patterson DF, Haskins MH. Globoid cell leukodystrophy in cairn and West Highland white terriers. Journal of Heredity 90:138-142, 1999.

Victoria T, Rafi MA, Wenger DA. Cloning of the canine GALC cDNA and identification of the mutation causing globoid cell leukodystrophy in West Highland White and Cairn Terriers. Genomics 33:457-462, 1996.

68. Globoid Cell Leukodystrophy or Krabbe Disease, (GLD); mutation originally found in Terriers

Disease Category Type
neuromuscular

Description
Globoid cell leukodystrophy is a neurologic lysosomal storage disease that causes severe neuronal degeneration. The underlying cause of the disorder is a deficiency of a lysosomal galactocerebrosidase enzyme. This enzyme deficiency causes defects in the production of myelin that protects and insulates neurons. This particular genetic variant has been found to cause GLD in West Highland White Terriers and Cairn Terriers. Globoid cell leukodystrophy is an autosomal recessive disorder.

Clinical Overview
GLD is characterized by muscle weakness, tremors, and ataxia (uncoordinated movement). Clinical signs of the disease also include behavioral changes, incoherence, blindness, and deficits in normal reflexes. GLD is a progressive condition in which the characteristic signs of the disease are first observed in the hind legs. The first signs of the disease can be seen in dogs 1-5 months of age. Affected dogs do not survive to adulthood and they are usually euthanized before 9 months of age.

Mutation Found In:
Cairn Terrier, West Highland White Terrier

Gene Variant Tested
GALC terriers

Clinical Signs
muscle weakness, ataxia, tremor, paralysis, and behavioral changes

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
McGraw RA, Carmichael KP. Molecular basis of globoid cell leukodystrophy in Irish setters. Vet J 171:370-2, 2006.

Wenger DA, Victoria T, Rafi MA, Luzi P, Vanier MT, Vite C, Patterson DF, Haskins MH. Globoid cell leukodystrophy in cairn and West Highland white terriers. Journal of Heredity 90:138-142, 1999.

Victoria T, Rafi MA, Wenger DA. Cloning of the canine GALC cDNA and identification of the mutation causing globoid cell leukodystrophy in West Highland White and Cairn Terriers. Genomics 33:457-462, 1996.

69. Glycogen Storage Disease Type Ia, (GSD Ia)

Disease Category Type
metabolic

Description
Glycogen storage disease type Ia (GSD Ia) is a severe metabolic disorder encountered in the Maltese. Failure of glucose metabolism causes glycogen accumulation leading to hypoglycemia, lactic acidosis causing low blood pH, coma, and death. The disease is inherited in an autosomal recessive manner.

Clinical Overview
GSD Ia-affected Maltese dogs have a congenital deficiency in the enzyme glucose-6-phosphatase required for breakdown of glycogen. Glycogen is a large polysaccharide that serves as energy storage in the body and an energy source for cells. Insufficient enzyme function causes cellular accumulation of glycogen especially in the liver and impairment of endogenous glucose production. GSD Ia is characterized by hypoglycemia (low blood sugar). Affected puppies are weak and they rarely survive more than few weeks.

Mutation Found In:
Maltese

Gene Variant Tested
G6PC

Clinical Signs
hepatomegaly, hypoglycemia, lactic acidosis, hyperuricemia, coma, and death

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kishnani PS, Faulkner E, VanCamp S, Jackson M, Brown T, Boney A, Koeberl D, Chen YT. Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia). Vet Pathol 38(1):83-91, 2001.

Kishnani PS, Bao Y, Wu JY, Brix AE, Lin JL, Chen YT. Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia. Biochem Mol Med 61(2):168-177, 1997.

Specht A, Fiske L, Erger K, Cossette T, Verstegen J, Campbell-Thompson M, Struck MB, Lee YM, Chou JY, Byrne BJ, Correia CE, Mah CS, Weinstein DA, Conlon TJ. Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease. J Biomed Biotechnol 2011:646257, 2011.

70. Glycogen Storage Disease Type IIIa, (GSD IIIa); mutation originally found in Curly Coated Retriever

Disease Category Type
metabolic

Description
Glycogen storage disease type IIIa is a disorder of glycogen metabolism affecting Curly Coated Retrievers. The clinical signs of GSD IIIa include fatigue, exercise intolerance, and hypoglycemic collapse caused by low blood sugar. Characteristic signs can be observed at around 14 months of age. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
GSD IIIa affected dogs have a congenital deficiency in the enzyme glycogen debranching enzyme required for breakdown of glycogen. Glycogen is a large polysaccharide that serves as energy storage in the body and an energy source for cells. Enzyme deficiency causes cellular glycogen accumulation in the liver and muscles and impairment of endogenous glucose production. The clinical signs of GSD IIIa include fatigue, exercise intolerance, and hypoglycemic collapses caused by low blood sugar. Characteristic signs can be observed at around 14 months of age.

Mutation Found In:
Curly Coated Retriever

Gene Variant Tested
AGL

Clinical Signs
fatigue, exercise intolerance, and episodic hypoglycemic collapse

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gregory BL, Shelton GD, Bali DS, Chen YT, Fyfe JC. Glycogen storage disease type IIIa in curly-coated retrievers. J Vet Intern Med 21:40-6, 2007.

71. GM2 Gangliosidosis; mutation originally found in Japanese Chin

Disease Category Type
neuromuscular

Description
GM2 gangliosidosis, is a lysosomal storage disease causing progressive degeneration of nervous tissue. The disorder is known to affect Japanese Chins and is also known as Tay-Sachs disease. A related condition is also seen in Toy Poodles and Golden Retrievers but the underlying mutation is still unknown in Golden Retrievers. Characteristic signs include ataxia (uncoordinated movements), intention tremors of the head, vision impairment, altered mental status, and feeding difficulties. GM2 gangliosidosis is a progressive condition and affected dogs are usually euthanized by two years of age. GM2 gangliosidosis is inherited as an autosomal recessive trait.

Clinical Overview
First signs of GM2 gangliosidosis are usually observed at one year of age. Characteristic signs include ataxia (uncoordinated movements), intention tremors of the head, vision impairment, altered mental status, and feeding difficulties. GM2 gangliosidosis is a progressive condition and affected dogs are usually euthanized by two years of age.

Mutation Found In:
Japanese Chin

Gene Variant Tested
HEXA

Clinical Signs
ataxia and intention tremors

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Matsuki N, Yamato O, Kusuda M, Maede Y, Tsujimoto H, Ono K. Magnetic resonance imaging of GM2-gangliosidosis in a golden retriever. Can Vet J 46(3):275-278, 2005.

Rahman MM, Chang HS, Mizukami K, Hossain MA, Yabuki A, Tamura S, Kitagawa M, Mitani S, Higo T, Uddin MM, Uchida K, Yamato O. A frameshift mutation in the canine HEXB gene in toy poodles with GM2 gangliosidosis variant 0 (Sandhoff disease). Vet J 194(3):412-416, 2012.

72. GM2 Gangliosidosis; mutation originally found in Toy Poodle

Disease Category Type
neuromuscular

Description
GM2 gangliosidosis, is a lysosomal storage disease causing progressive degeneration of nervous tissue. The disorder is known to affect Toy Poodle and is also known as Sandhoff disease. A related condition is also seen in Japanese Chins and Golden Retrievers but the underlying mutation is still unknown in Golden Retrievers. Characteristic signs include ataxia (uncoordinated movements), intention tremors of the head, vision impairment, altered mental status, and feeding difficulties. GM2 gangliosidosis is a progressive condition and affected dogs are usually euthanized by two years of age. GM2 gangliosidosis is inherited as an autosomal recessive trait.

Clinical Overview
First signs of GM2 gangliosidosis are usually observed at one year of age. Characteristic signs include ataxia (uncoordinated movements), intention tremors of the head, vision impairment, altered mental status, and feeding difficulties. GM2 gangliosidosis is a progressive condition and affected dogs are usually euthanized by two years of age.

Mutation Found In:
Toy Poodle

Gene Variant Tested
HEXB

Clinical Signs
ataxia and intention tremors

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Matsuki N, Yamato O, Kusuda M, Maede Y, Tsujimoto H, Ono K. Magnetic resonance imaging of GM2-gangliosidosis in a golden retriever. Can Vet J 46(3):275-278, 2005.

Rahman MM, Chang HS, Mizukami K, Hossain MA, Yabuki A, Tamura S, Kitagawa M, Mitani S, Higo T, Uddin MM, Uchida K, Yamato O. A frameshift mutation in the canine HEXB gene in toy poodles with GM2 gangliosidosis variant 0 (Sandhoff disease). Vet J 194(3):412-416, 2012.

73. Hereditary Ataxia or Cerebellar Ataxia; mutation originally found in Old English Sheepdog and Gordon Setter

Disease Category Type
neurologic

Description
Hereditary ataxias are a heterogeneous group of disorders characterized by neuronal degeneration of the cerebellar cortex and are also known as cerebellar abiotrophy or cerebellar cortical degeneration in dogs. Degeneration of the cerebellar nerve cells leads to progressive ataxia (lack of normal coordination of movement). The onset of clinical signs and pattern of progression varies in different forms of the condition. The onset of clinical signs can be in puppyhood, at a young age, or in adulthood depending on the form of the cerebellar ataxia. Hereditary cerebellar ataxia in Old English Sheepdogs and Gordon Setters is a slowly progressing, early-onset form of hereditary ataxia caused by a mutation in RAB24 gene. The disorder is inherited as an autosomal recessive trait.

Clinical Overview
In Old English Sheepdogs, the first signs of cerebellar ataxia are usually observed at 6 months to 4 years of age. The onset of clinical signs in Gordon Setters is usually at the age of 6 to 10 months. Characteristic signs include ataxia (uncoordinated movements) and hypermetria (overreaching movements). Intention tremors, wide-based stance, and nystagmus (involuntary eye movements) are also observed on occasion. Cerebellar ataxia is a slowly progressing condition in both breeds.

Mutation Found In:
Gordon Setter, Old English Sheepdog

Gene Variant Tested
RAB24

Clinical Signs
progressive ataxia, hypermetria, intention tremors, and wide-based stance

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Agler C, Nielsen DM, Urkasemsin G, Singleton A, Tonomura N, Sigurdsson S, Tang R, Linder K, Arepalli S, Hernandez D, Lindblad-Toh, K, van de Leemput J, Motsinger-Reif A, O'Brien, DP, Bell J, Harris T, Steinberg S, Olby N.J Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24. PLoS Genet 10:e1003991, 2014.

Steinberg HS, Troncoso JC, Cork LC, Price DL. Clinical features of inherited cerebellar degeneration in Gordon setters. J Am Med Assoc 1981;179:886-890.

Steinberg HS, Van Winkle T, Bell JS, de Lahunta A. Cerebellar degeneration in Old English Sheepdogs. J Am Vet Med Assoc 2000;217:1162-1165.

74. Hereditary Elliptocytosis

Disease Category Type
blood

Description
Hereditary elliptocytosis is characterized by abnormally shaped red blood cells or erythrocytes in the blood. Abnormal cells have an oval shape instead of the characteristic biconcave shape of canine erythrocytes. Abnormally shaped red blood cells are called elliptocytes or ovalocytes. The genetic background of canine congenital elliptocytosis remains poorly understood.

Clinical Overview
Most typically, canine hereditary elliptocytosis is encountered as an asymptomatic condition that is detected during examination of the dog for an unrelated disease. Only one genetic mutation associated with elliptocytosis was previously described. In a case study on one dog, a Labrador x Chow Chow mixed breed, the patient presented with persistent elliptocytosis, decreased mechanical deformability of erythrocytes and decreased erythrocyte membrane stability. Molecularly, elliptocytosis was found to be due to a defect in the erythrocyte membrane protein β-spectrin. The studied dog was found to be heterozygous for a mutation in the β-spectrin encoding gene. Further information on the mutation is needed to examine whether homozygosity for the mutation leads to a more severe hemolytic, elliptocytic anemia.

Mutation Found In:
Chow Chow, Labrador Retriever, Mixed breed

Gene Variant Tested
SPTB

Clinical Signs
abnormal oval shaped red blood cells and possible hemolytic anemia

Mode of Inheritance
autosomal dominant

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Conboy JG, Shitamoto R, Parra M, Winardi R, Kabra A, Smith J, Mohandas N Hereditary elliptocytosis due to both qualitative and quantitative defects in membrane skeletal protein 4.1. Blood. 1;78(9):2438-2443, 1991.

Di Terlizzi R, Gallagher PG, Mohandas N, Steiner LA, Dolce KS, Guo X, Wilkerson MJ, Stockham SL. Canine elliptocytosis due to a mutant beta-spectrin. Vet Clin Pathol 38(1):52-8, 2009.

75. Hereditary Footpad Hyperkeratosis, (HFH)

Disease Category Type
dermal

Description
Hereditary footpad hyperkeratosis (HFH) is a congenital skin disorder encountered in the Kromfohrländer and the Irish Terrier. The disorder is characterized by hard, thickened, and cracked footpads and an abnormal coat. Hereditary footpad hyperkeratosis is inherited in an autosomal recessive manner.

Clinical Overview
Hereditary footpad hyperkeratosis is a progressive condition characterized by dry and thickened footpads. The clinical signs include painful cracks and fissures on the footpads that may lead to secondary infections and lameness. Horny protrusions can be observed on all footpads. Affected dogs often avoid walking on rough surfaces. The signs result from abnormal keratinous proliferation of cells of the skin. Typical signs of hereditary footpad hyperkeratosis are observable in all four feet by the age of 4-5 months. Other characteristic signs are hard nails that seem to grow fast and a soft, dull, and less-wiry coat. Dogs suffering from hereditary hyperkeratosis have a normal lifespan if the footpads and nails are cared for appropriately.

Mutation Found In:
Irish Terrier, Kromfohrländer

Gene Variant Tested
FAM83G

Clinical Signs
hard and cracked footpads and a dull, less wiry, softer coat

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Drögemüller M, Jagannathan V, Becker D, Drögemüller C, Schelling C, Plassais J, Kaerle C, Dufaure de Citres C, Thomas A, Müller EJ, Welle MM, Roosje P, Leeb T. A Mutation in the FAM83G Gene in Dogs with Hereditary Footpad Hyperkeratosis (HFH). PLoS Genet 10(5): e1004370, 2014.

76. Hereditary Vitamin D-Resistant Rickets Type II, (HVDRR)

Disease Category Type
skeletal

Description
Hereditary vitamin D-resistant rickets (HVDRR) is characterized by defects in the vitamin D receptors of the end-organs. Bone mineralization is inhibited in HVDRR causing softening and bending of the bones and skeletal malformations. The clinical signs of HVDRR include limb deformities and joint pain. The causative mutation for HVDRR has been identified in Pomeranians. The condition is inherited as an autosomal recessive trait.

Clinical Overview
The underlying cause for hereditary vitamin D-resistant rickets is a defect in the vitamin D receptor that prevents vitamin D from reaching its target tissues. HVDRR is characterized by low calcium levels leading to secondary hyperparathyroidism. Vitamin D enhances bone mineralization and calcium is essential for hardness and strength of the bones. Vitamin D-resistance causes dysfunctional bone mineralization leading to the softening of bones and skeletal deformities. The clinical signs of HVDRR include joint pain, lameness, limb deformities, spontaneous fractures, jaw deformities, and neurological signs. HVDRR can also cause alopecia (hairlessness). Affected dogs can be treated by oral administration of active vitamin D and calcium supplements. The bone deformities are, however, irreversible.

Mutation Found In:
Pomeranian

Gene Variant Tested
VDR

Clinical Signs
hypocalcemia, secondary hyperparathyroidism, hypomineralization of bones, bone malformations, rickets, joint pain, lameness, limb deformities, spontaneous fractures, and alopecia

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
LeVine DN, Zhou Y, Ghiloni RJ, Fields EL, Birkenheuer AJ, Gookin JL, Roberston ID, Malloy PJ, Feldman D. Hereditary 1,25-dihydroxyvitamin D-resistant rickets in a Pomeranian dog caused by a novel mutation in the vitamin D receptor gene. J Vet Intern Med23:1278-83, 2009.

77. Hyperekplexia or Startle Disease

Disease Category Type
neurologic

Description
Hyperekplexia or startle disease is a rare congenital disorder encountered in Irish Wolfhounds. The first clinical signs of hyperekplexia can be seen in very young puppies. Affected puppies suffer from muscle stiffness and tremor when handled, and are usually euthanized before three months of age. Hyperekplexia is inherited as an autosomal recessive trait.

Clinical Overview
The first clinical signs of hyperekplexia can be observed in one week old puppies. The affected puppies respond to handling with rigid limbs and tremors. Relaxation or sleeping eases the clinical signs. Affected puppies have difficulties standing and they develop a stiff posture with all four limbs extended. Cyanosis or bluish discoloration of mucous membranes is also characteristic of hyperekplexia. Cyanosis can be observed especially when an affected puppy is nursing. The condition is severe and progressive. Affected puppies are usually euthanized before three months of age.

Mutation Found In:
Irish Wolfhound

Gene Variant Tested
SLC6A5

Clinical Signs
muscle stiffness, tremor, difficulty or inability to stand, rigid posture, and cyanosis

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gill JL, Capper D, Vanbellinghen JF, Chung SK, Higgins RJ, Rees MI, Shelton GD, Harvey RJ. Startle disease in Irish wolfhounds associated with a microdeletion in the glycine transporter GlyT2 gene. Neurobiol Dis 43(1):184-189, 2011.

78. Hyperuricosuria, (HUU)

Disease Category Type
renal

Description
Hyperuricosuria (HUU) is an inherited disorder in dogs that can cause hyperuricemia and predisposes affected dogs to the development of urolithiasis (urate stones) in the kidneys and bladder. The disease is very common in Dalmatians but is seen in several other breeds as well. Hyperuricosuria is inherited in an autosomal recessive manner.

Clinical Overview
HUU predisposes affected dogs to the formation of uric acid stones. In Dalmatians, the disease is more common in males than in females. As much as 34% of all male Dalmatians are diagnosed with uric acid stones. Clinical signs of urolithiasis include hematuria, pain while urinating, and blockage of the urinary tract. Patients with urine stones are more susceptible to urinary tract infections. Blockage of the urinary tract is a life-threatening condition that requires immediate veterinary care. The condition can be partly managed through diet therapy.

Mutation Found In:
American Bulldog, American Pit Bull Terrier, American Staffordshire Terrier, Australian Shepherd, Black Russian Terrier, Boerboel, Bulldog, Dalmatian, German Shepherd Dog, German Spitz, Giant Schnauzer, Jack Russell Terrier, Labrador Retriever, Lagotto Romagnolo, Large Munsterlander, Miniature American Shepherd, Mixed breed, Parson Russell Terrier, Pomeranian, Spanish Water Dog, Wirehaired Vizsla, Weimaraner

Gene Variant Tested
SLC2A9

Clinical Signs
urolithiasis and hyperuricemia

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Bannasch D, Safra N, Young A, Karmi N, Schaible GV, Ling GV. Mutations in the SLC2A9 Gene Cause Hyperuricosuria and Hyperuricemia in the Dog. PLoS Genet 4(11):e1000246, 2008.

Karmi N, Brown EA, Hughes SS, Mclaughlin B, Mellersh CS, Biourge V, Bannasch DL. Estimated frequency of the canine hyperuricosuria mutation in different dog breeds. J Vet Intern Med 24:1337-42, 2010.

79. Hypocatalasia or Acatalasemia

Disease Category Type
metabolic

Description
Hypocatalasia, the deficiency of catalase enzyme activity in red blood cells, has been studied in Beagles. The catalase enzyme plays an important role in the cellular defense against oxidative damage. The disorder has only been recognized in a laboratory colony of Beagles. The acatalasemia phenotype caught particular interest as an animal model of a human condition called Takahara's disease. The disorder is characterized by ulcers and progressive gangrene (tissue death) of the oral cavity. To our knowledge, the disorder is inherited as an autosomal trait, but the exact mode of inheritance is yet to be confirmed. Carriers may potentially show some degree of clinical signs.

Clinical Overview
The clinical signs of hypocatalasia in dogs have not been described properly in the literature but include progressive gangrene in the oral cavity. In the human condition, the severity of signs can vary remarkably. The erythrocytes of affected dogs show no signs of catalase activity.

Mutation Found In:
Beagle

Gene Variant Tested
CAT

Clinical Signs
progressive gangrene in the oral cavity

Mode of Inheritance
recessive but may also affect some heterozygotes

Signs Seen in Affected Carriers
mild clinical signs

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Nakamura K, Watanabe M, Takanaka K, Sasaki Y, Ikeda T. cDNA cloning of mutant catalase in acatalasemic beagle dog: single nucleotide substitution leading to thermal-instability and enhanced proteolysis of mutant enzyme. Int J Biochem Cell Biol 32:1183-1193, 2000.

Nakamura K, Watanabe M, Sasaki Y, Ikeda T. Purification and characterization of liver catalase in acatalasemic beagle dog: comparison with normal dog liver catalase. Int J Biochem Cell Biol 32:89-98, 2000.

Ogata M, Wang DH, Ogino K. Mammalian acatalasemia: the perspectives of bioinformatics and genetic toxicology. Acta Med Okayama 62(6):345-361, 2008.

Nakamura, K, Watanabe, M, Ikeda, T, Sasaki, Y, Matsunuma, N. Tissue and organ expression of catalase in acatalasemic beagle dogs. Exp Anim. 1999 Oct;48(4):229-34.

80. Hypomyelination; mutation originally found in Weimaraner

Disease Category Type
neurologic

Description
Hypomyelination in Weimaraner dogs is an inherited neurological disorder characterized by delayed myelination of the central nervous system. Myelin is an insulating substance surrounding the axons of the cells of the central nervous system. Hypomyelination causes generalized tremors in puppyhood. The disorder has been described in several other dog breeds, but the causative mutations remain unknown. Hypomyelination is inherited in an autosomal recessive manner in Weimaraners.

Clinical Overview
The onset of signs typically occurs at 1-2 weeks of age. A characteristic sign of hypomyelination is muscle tremor. The severity of the tremor can vary between individuals, however body tremors tend to worsen with activity (action tremor) and decline during rest. Affected dogs are able to walk, but they may have a "hopping-like movement of the hind legs. Affected puppies usually improve by 3-4 months of age, although some dogs may continue to exhibit a mild persistent tremor of the hind legs.

Mutation Found In:
Weimaraner

Gene Variant Tested
FNIP2

Clinical Signs
action tremors and locomotory difficulties

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Pemberton TJ, Choi S, Mayer JA, Li FY, Gokey N, Svaren ., Safra N, Bannasch DL, Sullivan K, Breuhaus B, Patel PI, Duncan ID. A mutation in the canine gene encoding folliculin-interacting protein 2 (FNIP2) associated with a unique disruption in spinal cord myelination. 62:39-51, 2014.

Millán Y, Mascort J, Blanco A, Costa C, Masian D, Guil-Luna S, Pumarola M, Martin de Las Mulas J. Hypomyelination in three Weimaraner dogs. J Small Anim Pract 51:594-8, 2010.

81. Ichthyosis; mutation originally found in Great Dane

Disease Category Type
dermal

Description
Ichthyoses are hereditary disorders affecting skin cornification. The genetic background and severity of clinical signs vary between different dog breeds. In Great Danes, the disease leads to severe, generalized hyperkeratosis of the skin promoting secondary infections. A causative mutation for the disease has been found in the breed. Symptoms are detectable in young puppies and often result in euthanasia. The mode of inheritance is autosomal recessive.

Clinical Overview
In affected Great Danes, the disease causes congenital, generalized, severe hyperkeratosis of the skin. Affected puppies are presented with a strongly wrinkled, thickened, dry, inelastic, scaling skin. The region around the eyes and nose are more strongly affected. In some cases, swelling and wrinkling of the skin around the eyes may impede the puppy from opening its eyes. Wrinkles in the exudative part of the skin promote severe secondary skin infections. Affected puppies may also have a displaced and wrinkled auditory canal. There is no cure and affected dogs are treated symptomatically though they are often euthanized by two months of age.

Mutation Found In:
Great Dane

Gene Variant Tested
SLC27A4

Clinical Signs
wrinkled, thickened skin; scaling skin; secondary skin infections

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Metzger J, Wöhlke A, Mischke R, Hoffmann A, Hewicker-Trautwein M, Küch E, Naim H, Distl O. A Novel SLC27A4 Splice Acceptor Site Mutation in Great Danes with Ichthyosis. PLoS ONE 10(10): e0141514, 2015.

82. Intestinal Cobalamin Malabsorption or Imerslund-Grasbeck Syndrome, (IGS); mutation originally found in Beagle

Disease Category Type
metabolic

Description
Intestinal cobalamin malabsorption or Imerslund-Gräsbeck syndrome (IGS) is a metabolic disorder encountered in several breeds. Failure to absorb cobalamin in the small intestine results in retarded growth, anemia, and neutropenia. The underlying cause for intestinal cobalamin malabsorption is a defect in cobalamin receptors in the ileum. Causative mutations have been identified in the AMN (amnionless) and CUBN (cubilin) genes. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Cobalamin or vitamin B12 is required for normal function of many enzymes. Cobalamin is stored in the body before birth, but once those stores are consumed early in life, cobalamin must to be acquired from food. Initial signs of intestinal cobalamin malabsorption can be seen in puppies 6-12 weeks of age. Puppies with IGS suffer from weakness and loss of appetite and fail to grow normally: anemia, neutropenia, and low cobalamin concentrations are present. High levels of homocysteine and methylmalonic acid can also be observed in the blood. Proteinuria is observable in the urine sample.

Mutation Found In:
Beagle, Mixed breed

Gene Variant Tested
CUBN Beagle

Clinical Signs
growth retardation, anemia, neutropenia, and loss of appetite

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Drögemüller M, Jagannathan V, Howard J, Bruggmann R, Drögemüller C, Ruetten M, Leeb T, Kook PH. A frameshift mutation in the cubilin gene (CUBN) in Beagles with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). Anim Genet 45(1):148-150, 2013.

Fyfe JC, Hemker SL, Venta PJ, Stebbing B, Giger U. Selective Intestinal Cobalamin Malabsorption with Proteinuria (Imerslund-Gräsbeck Syndrome) in Juvenile Beagles. J Vet Intern Med 28(2):356-362, 2014.

Fyfe JC, Giger U, Hall CA, Jezyk PF, Klumpp SA, Levine JS, Patterson DF. Inherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs. Pediatr Res 29(1):24-31, 1991.

Fyfe JC, Ramanujam KS, Ramaswamy K, Patterson DF, Seetharam B. Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption. J Biol Chem 266(7):4489-4494, 1991.

Owczarek-Lipska M, Jagannathan V, Drögemüller C, Lutz S, Glanemann B, Leeb T, Kook PH. A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). PLoS One 8:e61144, 2013.

83. Intestinal Cobalamin Malabsorption or Imerslund-Grasbeck Syndrome, (IGS); mutation originally found in Border Collie

Disease Category Type
metabolic

Description
Intestinal cobalamin malabsorption or Imerslund-Gräsbeck syndrome (IGS) is a metabolic disorder encountered in several breeds. Failure to absorb cobalamin in the small intestine results in retarded growth, anemia, and neutropenia. The underlying cause for intestinal cobalamin malabsorption is a defect in cobalamin receptors in the ileum. Causative mutations have been identified in the AMN (amnionless) and CUBN (cubilin) genes. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Cobalamin or vitamin B12 is required for normal function of many enzymes. Cobalamin is stored in the body before birth, but once those stores are consumed early in life, cobalamin must to be acquired from food. Initial signs of intestinal cobalamin malabsorption can be seen in puppies 6-12 weeks of age. Puppies with IGS suffer from weakness and loss of appetite and fail to grow normally: anemia, neutropenia, and low cobalamin concentrations are present. High levels of homocysteine and methylmalonic acid can also be observed in the blood. Proteinuria is observable in the urine sample.

Mutation Found In:
Border Collie, Mixed breed

Gene Variant Tested
CUBN Border Collie

Clinical Signs
growth retardation, anemia, neutropenia, and loss of appetite

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Drögemüller M, Jagannathan V, Howard J, Bruggmann R, Drögemüller C, Ruetten M, Leeb T, Kook PH. A frameshift mutation in the cubilin gene (CUBN) in Beagles with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). Anim Genet 45(1):148-150, 2013.

Fyfe JC, Hemker SL, Venta PJ, Stebbing B, Giger U. Selective Intestinal Cobalamin Malabsorption with Proteinuria (Imerslund-Gräsbeck Syndrome) in Juvenile Beagles. J Vet Intern Med 28(2):356-362, 2014.

Fyfe JC, Giger U, Hall CA, Jezyk PF, Klumpp SA, Levine JS, Patterson DF. Inherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs. Pediatr Res 29(1):24-31, 1991.

Fyfe JC, Ramanujam KS, Ramaswamy K, Patterson DF, Seetharam B. Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption. J Biol Chem 266(7):4489-4494, 1991.

Owczarek-Lipska M, Jagannathan V, Drögemüller C, Lutz S, Glanemann B, Leeb T, Kook PH. A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption). PLoS One 8:e61144, 2013.

84. Juvenile Laryngeal Paralysis and Polyneuropathy, (JLPP, POANV); mutation originally found in Black Russian Terrier and Rottweiler

Disease Category Type
neurologic

Description
Disorders resembling the human Warburg micro syndrome are seen in dogs. These disorders are characterized by polyneuropathy with ocular abnormalities and neuronal vacuolization (referred as POANV). The subtypes exhibit different characteristics and affect different breeds. In Black Russian Terriers and Rottweilers, the disorder is commonly referred to as juvenile laryngeal paralysis and polyneuropathy. These disorders are inherited in an autosomal recessive fashion.

Clinical Overview
Difficulty breathing due to laryngeal paralysis is a severe but very typical clinical sign associated with the disorder in Black Russian Terriers and Rottweilers. Affected puppies develop noticeable problems with inspiration at around 3 months of age. Laryngeal paralysis also causes problems in swallowing, creating a risk for aspiration pneumonia. These puppies may also have evidence of ocular signs such as microphthalmia. The progression of the disease is fast and affected puppies are euthanized soon after diagnosis.

Alaskan Huskies, on the other hand, do not develop laryngeal paralysis and breathing problems. Alaskan Huskies typically develop clinical signs at around 4-5 months of age. Typical clinical signs include uncoordinated movement, weakness, visual impairment, and regurgitation. Affected dogs also have microphthalmia and other ocular abnormalities. The disease is progressive and affected dogs are euthanized at a young age.

Mutation Found In:
Black Russian Terrier, Rottweiler, Alaskan Malamute

Gene Variant Tested
RAB3GAP1:c.743delC

Clinical Signs
ataxia, weakness, microphthalmia, laryngeal paralysis

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Mhlanga-Mutangadura T, Johnson GS, Ashwini A, Shelton GD, Wennogle SA, Johnson GC, Kuroki K, O'Brien DP. A Homozygous RAB3GAP1:c.743delC Mutation in Rottweilers with Neuronal Vacuolation and Spinocerebellar Degeneration. J Vet Intern Med. 2016 May;30(3):813-8. doi: 10.1111/jvim.13921. Epub 2016 Mar 10.

85. Juvenile Myoclonic Epilepsy, (JME)

Disease Category Type
neurologic

Description
Juvenile Myoclonic Epilepsy is a specific form of epilepsy that has been described in Rhodesian Ridgebacks. As the name states, clinical signs emerge at a young age. First signs of the diseases are muscle jerks/twitches which can progress to generalized seizures. Epileptiform activity is triggered usually by resting or by visual stimulus (light). The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Clinical signs of the disease typically emerge around 6 months of age but the age of onset can vary from as young as 6 weeks of age to 1.5 years of age. Clinical signs begin with myoclonic jerks/twitches or the trunk, forelimbs, and nodding of the head. The appearance can resemble severe startling or even an electric shock. Twitches of varying intensity are most commonly seen in relaxed dogs that are beginning to sleep. The frequency of these twitches can be very high, even 150 twitches per day. The ability to sleep and rest is thus impaired. Affected dogs can also be sensitive to light with visual stimulus triggering epileptiform activity. Approximately 38% of affected dogs progress to having generalized tonic-clonic seizures. Biological factors, such as vaccination or heat might affect the frequency and/or beginning of symptoms.

Mutation Found In:
Rhodesian Ridgeback

Gene Variant Tested
DIRAS1

Clinical Signs
myoclonic jerks during rest or after visual stimulus

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wielaendera F, Sarviaho R, Jamese F, Hytönen M, Cortez M, Klugerh G, Koskinen L, Arumilli M, Kornbergj M, Bathen-Noethenk A, Tipoldl A, Rentmeisterm K, Bhattin S, Hülsmeyera V, Boettchero I, Tästenseno C, Flegelo T, Dietschip E, Leebp T, Matiasekq K, Fischera A, and Lohi H. Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1. doi: 10.1073/pnas.1614478114

86. L-2-Hydroxyglutaric Aciduria, (L2HGA); mutation originally found in Staffordshire Bull Terrier

Disease Category Type
neurologic

Description
L-2-hydroxyglutaric aciduria (L2HGA) is an inherited inborn error of intermediary metabolism found primarily in Staffordshire Bull Terriers. The mutation causes the enzyme that breaks down L-2-hydroxyglutaric acid to be defective and therefore concentrations in the body increase; high concentrations are particularly toxic to tissues in the central nervous system. Typically, the disease presents itself between six months and one year of age but can be presented as late as seven years of age, with neurologic clinical signs including: ataxia, muscle stiffness at exercise or excitement, altered behavior, or epileptic seizures. The disease is inherited in an autosomal recessive manner.

Clinical Overview
Dogs affected by L-2-hydroxyglutaric aciduria (L2HGA) have a mutation in the gene that codes for the mitochondrial membrane enzyme called L-2-hydroxyglutarate dehydrogenase that breaks down L-2-hydroxyglutaric acid. Because of the mutation, levels of L-2-hydroxyglutaric acid accumulate in the body, where high concentrations are particularly toxic to the central nervous system. Typically, the disease presents itself between six months and one year of age but can be presented as late as seven years of age, with neurologic clinical signs including: ataxia, muscle stiffness at exercise or excitement, altered behavior, or epileptic seizures. While there is no cure, palliative treatment for the clinical signs associated with the disease can improve the quality of life for the dog. Seizures do generally respond to standard anti-epileptic therapy, such as phenobarbital. L2HGA is inherited in an autosomal recessive manner in dogs.

Mutation Found In:
Staffordshire Bull Terrier

Gene Variant Tested
L2HGDH Staffordshire Bull Terrier

Clinical Signs
ataxia, muscle stiffness at exercise or excitement, altered behavior, and epileptic seizures

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Farias FH, Zeng R, Johnson GS, Shelton GD, Paquette D, O'Brien DP. A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria. BMC Vet Res 8:124, 2012.

Sanchez-Masian DF, Artuch R, Mascort J, Jakobs C, Salomons G, Zamora A, Casado M, Fernandez M, Recio A, Lujan A. L-2-hydroxyglutaric aciduria in two female Yorkshire terriers. J Am Anim Hosp Assoc 48:366-71, 2012.

Penderis, J, Calvin, J, Abramson, C, Jakobs, C, Pettitt, L, Binns,MM, Verhoeven, NM, O'Driscoll, E, Platt, SR, Mellersh, CS. L-2-hydroxyglutaric aciduria: characterization of the molecular defect in a spontaneous canine model. J Med Genet 44:334-40, 2007.

Garosi LS, Penderis J, McConnell JF, Jakobs C. L-2-hydroxyglutaric aciduria in a West Highland white terrier. Vet Rec 156:145-7, 2005.

Abramson CJ, Platt SR, Jakobs C, Verhoeven NM, Dennis R, GarosiL, Shelton GD. L-2-Hydroxyglutaric aciduria in Staffordshire Bull Terriers. J Vet Intern Med 17:551-6, 2003.

87. L-2-Hydroxyglutaric Aciduria, (L2HGA); mutation originally found in West Highland White Terrier

Disease Category Type
neurologic

Description
L-2-hydroxyglutaric aciduria (L2HGA) is an inherited inborn error of intermediary metabolism found primarily in Staffordshire Bull Terriers and West Highland White Terriers. The mutation causes the enzyme that breaks down L-2-hydroxyglutaric acid to be defective and therefore concentrations in the body increase; high concentrations are particularly toxic to tissues in the central nervous system. Typically, the disease presents itself between six months and one year of age but can present as late as seven years of age, with neurologic clinical signs including: ataxia, muscle stiffness at exercise or excitement, altered behavior, or epileptic seizures. The disease is inherited in an autosomal recessive manner.

Clinical Overview
Dogs affected by L-2-hydroxyglutaric aciduria (L2HGA) have a mutation in the gene that codes for the mitochondrial membrane enzyme called L-2-hydroxyglutarate dehydrogenase that breaks down L-2-hydroxyglutaric acid. Because of the mutation, levels of L-2-hydroxyglutaric acid accumulate in the body, where high concentrations being particularly toxic to the central nervous system. Typically, the disease presents itself between six months and one year of age but can be presented as late as seven years of age, with neurologic clinical signs including: ataxia, muscle stiffness at exercise or excitement, altered behavior, or epileptic seizures. While there is no cure, palliative treatment for the clinical signs associated with the disease can improve the quality of life for the dog. Seizures do generally respond to standard anti-epileptic therapy, such as phenobarbital. L2HGA is inherited in an autosomal recessive manner in dogs.

Mutation Found In:
West Highland White Terrier

Gene Variant Tested
L2HGDH West Highland White Terrier

Clinical Signs
ataxia, muscle stiffness at exercise or excitement, altered behavior, and epileptic seizures

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Farias FH, Zeng R, Johnson GS, Shelton GD, Paquette D, O'Brien DP. A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria. BMC Vet Res 8:124, 2012.

Sanchez-Masian DF, Artuch R, Mascort J, Jakobs C, Salomons G, Zamora A, Casado M, Fernandez M, Recio A, Lujan A. L-2-hydroxyglutaric aciduria in two female Yorkshire terriers. J Am Anim Hosp Assoc 48:366-71, 2012.

Penderis, J, Calvin, J, Abramson, C, Jakobs, C, Pettitt, L, Binns,MM, Verhoeven, NM, O'Driscoll, E, Platt, SR, Mellersh, CS. L-2-hydroxyglutaric aciduria: characterization of the molecular defect in a spontaneous canine model. J Med Genet 44:334-40, 2007.

Garosi LS, Penderis J, McConnell JF, Jakobs C. L-2-hydroxyglutaric aciduria in a West Highland white terrier. Vet Rec 156:145-7, 2005.

Abramson CJ, Platt SR, Jakobs C, Verhoeven NM, Dennis R, GarosiL, Shelton GD. L-2-Hydroxyglutaric aciduria in Staffordshire Bull Terriers. J Vet Intern Med 17:551-6, 2003.

88. Lagotto Storage Disease, (LSD)

Disease Category Type
neurologic

Description
Lagotto storage disease (LSD) is a progressive neurological disorder characterized by cerebellar ataxia. Histological examination reveals neuronal vacuolization in the peripheral and central nervous systems. Aggregation of vacuoles can also be seen in several other tissues, but only vacuolization of the nerve cells seems to be relevant. Lagotto storage disease affects the Lagotto Romagnolo breed. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
The onset of clinical signs and pattern of progression vary considerably between individuals. The first signs can be seen at the age of 4 months to 4 years. Typically the first observable sign of LSD is usually progressive ataxia (uncoordinated movements), which may not be noticed by the owner. Some of the affected dogs also suffer from episodic nystagmus (involuntary eye movement). In some cases, nystagmus is the first sign noticed. Lagotto storage disease is a progressive condition leading to behavioral changes such as restlessness, depression, and aggression. The life expectancy of affected dogs depends on the progression of the disorder and the severity of the signs. Some dogs can live for several years with mild signs, but dogs with severe clinical signs are usually euthanized earlier.

Mutation Found In:
Lagotto Romagnolo

Gene Variant Tested
ATG4D

Clinical Signs
ataxia, episodic nystagmus and changes in behavior (restlessness, depression, and aggression)

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kyöstilä K, Syrjä P, Jagannathan V, Chanddrasekar G, Jokinen TS, Seppälä EH, becker D, Drögemuller M, Dietschi E, Drögemuller C, Lang J, Steffen F, Rohdin C, Jäderlund KH, Lappalainen AK, Hahn K, Wohlsein P, Baumgärtner W, Henke D, Oevermann A, Kere J, Lohi H, Leeb T. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease. PLoS Genet 2015 Apr 15;11(4):e1005169.

89. Lamellar Ichthyosis

Disease Category Type
dermal

Description
Lamellar ichthyosis is a skin disorder causing severe hyperkeratosis (skin thickening) in Jack Russell Terriers. Affected dogs have thick, large scales around their body that can be either adherent or loose. Affected dogs are also susceptible to secondary bacterial and yeast skin infections. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
The first signs of LI can be seen in young puppies. Affected dogs have adherent or loose thick, large scales (0.5 - 2 cm) that are either white or tan in color and cover their body. Hyperkeratosis of the footpads and soft nails are also common clinical signs. Affected dogs often have chronic secondary bacterial and yeast infections on their skin.

Mutation Found In:
Jack Russell Terrier

Gene Variant Tested
TGM1

Clinical Signs
large, adherent or loose scales, bacterial and yeast infections on skin

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Credille KM, Minor JS, Barnhart KF, Lee E, Cox ML, Tucker KA, Diegel KL, Venta PJ, Hohl D, Huber M, Dunstan RW. Transglutaminase 1-deficient recessive lamellar ichthyosis associated with a LINE-1 insertion in Jack Russell terrier dogs. Br J Dermatol 161(2):265-272, 2009.

90. Ligneous Membranitis

Disease Category Type
dermal

Description
Ligneous membranitis is a rare hereditary inflammatory disease of the mucous membranes. The disease is chronic and causes progressive ulcerative conjunctivitis, stomatitis, and gingivitis. Affected dogs may also have nasal discharge, loud respiratory sounds, and enlarged lymph nodes. The disease is caused by a plasminogen deficiency. A causative mutation for the disease has been found in Scottish Terriers. The mode of inheritance is autosomal recessive.

Clinical Overview
Clinical signs of the disease include progressive oral and ocular inflammatory lesions. Affected dogs may have ulcerative inflammation in the mouth and the conjunctiva of the eyes. Other clinical signs include nasal discharge, loud respiratory sounds, and enlarged lymph nodes. Blood sampling may show neutrophilia, proteinuria, and hypoalbuminemia as well as low plasminogen activity. Affected dogs may have inflammatory fibrinous changes in the trachea, larynx, and in the thoracic and abdominal cavities. The prognosis of the disease is grave.

Mutation Found In:
Scottish Terrier

Gene Variant Tested
PLG Scottish Terrier

Clinical Signs
ulcerative conjunctivitis, ulcerative stomatitis, ulcerative gingivitis

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Ainsworth S, Carter S, Fisher C, Dawson J, Makrides L, Nuttall T, Mason S. Ligneous membranitis in Scottish Terriers is associated with a single nucleotide polymorphism in the plasminogen (PLG) gene. Anim Genet. Dec;46(6):707-710, 2015.

91. Macrothrombocytopenia; disease-linked variant originally found in Norfolk and Cairn Terrier

Disease Category Type
blood

Description
Congenital macrothrombocytopenia is a blood disorder characterized by oversized platelets and a low platelet count. The original mutation was first identified in the Cavalier King Charles Spaniel and is known to cause macrothrombocytopenia in several other breeds as well. This particular mutation variant however has been identified in Norfolk Terriers and Cairn Terriers. Congenital macrothrombocytopenia is inherited as an autosomal recessive trait.

Clinical Overview
Platelets, also called thrombocytes, are produced in the bone marrow. Platelets play an important role in the blood clotting system when a blood vessel is injured. Congenital macrothrombocytopenia is characterized by oversized platelets, also called macroplatelets, and an abnormally low number of platelets. Macroplatelets function normally and the affected dogs do not exhibit any health problems due to either the size or the fewer numbers of its platelets. Macrothrombocytopenia is not associated with spontaneous bleeding; however, it is important not to mistake macrothrombocytopenia for other more severe conditions characterized by low platelet counts.

Mutation Found In:
Cairn Terrier, Norfolk Terrier

Gene Variant Tested
TUBB1 terriers

Clinical Signs
low platelet count and macroplatelets

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gelain ME, Tutino GF, Pogliani E, Bertazzolo W. Macrothrombocytopenia in a group of related Norfolk terriers. Vet Rec 167:493-4, 2010.

Davis B, Toivio-Kinnucan M, Schuller S, Boudreaux MK. Mutation in beta1-tubulin correlates with macrothrombocytopenia in Cavalier King Charles Spaniels. J Vet Intern Med 22:540-5, 2008.

92. May-Hegglin Anomaly, (MHA)

Disease Category Type
blood

Description
May-Hegglin anomaly (MHA) is a blood disorder described in Pugs. MHA causes deficiency and structural abnormalities of blood platelet cells. The mode of inheritance has not been confirmed but autosomal dominant is the most probable.

Clinical Overview
Platelets of affected dogs are bigger and their numbers are lower than usual. In addition, there are changes in neutrophils. The disease does not usually cause clinical signs, although bruising or bleeding tendencies may be noted during surgery. Human patients have been reported to develop renal disease, hearing problems, and cataracts, but these signs have not been observed in Pugs.

Mutation Found In:
Pug

Gene Variant Tested
MYH9

Clinical Signs
platelet deficiency and large platelets

Mode of Inheritance
autosomal dominant

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Flatland B, Fry MM, Baek SJ, Bahn JH, LeBlanc CJ, Dunlap JR, Carroll RC, Kosiba DJ, Millsaps DJ, Schleis SE. May-Hegglin anomaly in a dog. Vet Clin Pathol 40(2):207-214, 2011.

93. Mucopolysaccharidosis Type IIIA, (MPS IIIA); mutation originally found in Dachshund

Disease Category Type
metabolic

Description
Mucopolysaccharidoses (MPS) are a group of rare inherited lysosomal storage disorders resulting from a deficiency in the enzymes required for degradation of glycosaminoglycans. Enzyme deficiency causes accumulation of metabolic by-products in cells disrupting their normal function. Several different forms of mucopolysaccharidoses with different clinical signs have been recognized in dogs. Type IIIA mucopolysaccharidosis (MPS IIIA) is encountered in Dachshunds and the New Zealand Huntaway. MPS IIIA is characterized by progressive neurological signs with little effect on bones and other organs as occurs in other forms of mucopolysaccharides. MPS IIIA is inherited in an autosomal recessive manner.

Clinical Overview
Mucopolysaccharidosis type IIIA is characterized by progressive ataxia (uncoordinated movements). The first signs of ataxia can be seen in pelvic limbs progressing later to all four limbs. The clinical signs include dysmetric gait and loss of balance. For example, climbing stairs becomes increasingly difficult as the disease progresses. An affected dog may also sway while standing. First clinical signs are usually observed in the third year of life. The affected dogs are usually euthanized a few years following the onset of clinical signs.

Mutation Found In:
Dachshund

Gene Variant Tested
SGSH Dachshund

Clinical Signs
pelvic limb ataxia, severe generalized spinocerebellar ataxia, hypermetria, and exaggerated reflexes

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Aronovich EL, Carmichael KP, Morizono H, Koutlas IG, Deanching M, Hoganson G, Fischer A, Whitley CB. Canine heparan sulfate sulfamidase and the molecular pathology underlying Sanfilippo syndrome type A in Dachshunds. Genomics 68:80-84, 2000.

Crawley AC, Marshall N, Beard H, Hassiotis S, Walsh V, King B, Hucker N, Fuller M, Jolly RD, Hopwood JJ, Hemsley KM. Enzyme replacement reduces neuropathology in MPS IIIA dogs. Neurobiol Dis 43:422-434, 2011.

Yogalingam G, Pollard T, Gliddon B, Jolly RD, Hopwood JJ.Identification of a mutation causing mucopolysaccharidosis type IIIA in New Zealand Huntaway dogs. Genomics 79:150-153, 2002.

94. Mucopolysaccharidosis Type VII, (MPS VII); mutation originally found in Brazilian Terrier

Disease Category Type
metabolic

Description
Mucopolysaccharidoses (MPS) are a group of rare inherited lysosomal storage disorders resulting from a deficiency in the enzymes required for degradation of glycosaminoglycans. Enzyme deficiency causes accumulation of metabolic by-products in cells disrupting their normal function. Several different forms of mucopolysaccharidoses with different clinical signs have been recognized in dogs. Mucopolysaccharidosis Type VII (MPS VII) is seen in the Brazilian Terrier and is characterized by severe skeletal dysplasia. Affected puppies show facial dysmorphia and have difficulty standing and moving due to the severe changes in bone structure. The mutation that causes MPS VII is inherited in an autosomal recessive manner, and affected puppies are usually euthanized because of the severity of the condition.

Clinical Overview
The first clinical signs of mucopolysaccharidosis VII can be seen in 2-4 week old puppies. Affected puppies show facial dysmorphia that includes a short broad face with low set ears. Affected dogs also have a broader body than their unaffected littermates. Affected puppies have difficulty standing and moving due to severe changes in the bone structure (spondyloepiphyseal dysplasia) and joint hyperlaxity. Affected puppies are usually euthanized because of the severity of the condition.

Mutation Found In:
Brazilian Terrier

Gene Variant Tested
GUSB Brazilian Terrier

Clinical Signs
dysmorphia, skeletal lesions, and death

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Hytönen MK, Arumilli M, Lappalainen AK, Kallio H, Snellman M, Sainio K, Lohi H. A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis. PLoS One 7:e40281, 2012.

Ray J, Bouvet A, Desanto C, Fyfe JC, Xu DB, Wolfe JH, Aguirre GD, Patterson DF, Haskins ME, Henthorn PS. Cloning of the canine beta-glucuronidase cDNA, mutation identification in canine MPS VII, and retroviral vector-mediated correction of MPS VII cells. Genomics 48:248-253, 1998.

Ray J, Scarpino V, Laing C, Haskins ME. Biochemical basis of the beta-glucuronidase gene defect causing canine mucopolysaccharidosis VII. J Hered 90:119-123, 1999.

95. Mucopolysaccharidosis Type VII, (MPS VII); mutation originally found in German Shepherd Dog

Disease Category Type
metabolic

Description
Mucopolysaccharidoses (MPS) are a group of rare inherited lysosomal storage disorders resulting from a deficiency in the enzymes required for degradation of glycosaminoglycans. Enzyme deficiency causes accumulation of metabolic by-products in cells disrupting their normal function. Several different forms of mucopolysaccharidoses with different clinical signs have been recognized in dogs. Mucopolysaccharidosis Type VII (MPS VII) is seen in the German Shepherd and is characterized by severe skeletal dysplasia; a variant is also seen in the Brazilian Terrier. Affected puppies show skeletal dysmorphia, corneal clouding, and have difficulty standing and moving due to the severe changes in bone structure and joint laxity. The mutation that causes MPS VII is inherited in an autosomal recessive manner, and affected puppies are usually euthanized because of the severity of the condition.

Clinical Overview
The first clinical signs of mucopolysaccharidosis VII can be seen in first clinical signs in dogs 2 to 5 months of age and typically involves hind limb weakness that progresses to ataxia of all four limbs The affected dogs also exhibit growth retardation, facial and other skeletal dysmorphisms, and corneal clouding. These dogs may show severe epiphyseal dysplasia when radiographed and exhibit extreme laxty of joints that can result in subluxation with minimal effort. Neutrophils and lymphocytes in the blood or CSF may have cytoplasmic granules. Several other organs can be present such as hepatomegaly, tracheal dysplasia, and cardiac abnormalities. Affected puppies are usually euthanized because of the severity of the condition.

Mutation Found In:
Germand Shepherd Dog

Gene Variant Tested
GUSB German Shepherd Dog

Clinical Signs
dysmorphia, skeletal lesions, and death

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Hytönen MK, Arumilli M, Lappalainen AK, Kallio H, Snellman M, Sainio K, Lohi H. A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis. PLoS One 7:e40281, 2012.

Ray J, Bouvet A, Desanto C, Fyfe JC, Xu DB, Wolfe JH, Aguirre GD, Patterson DF, Haskins ME, Henthorn PS. Cloning of the canine beta-glucuronidase cDNA, mutation identification in canine MPS VII, and retroviral vector-mediated correction of MPS VII cells. Genomics 48:248-253, 1998.

Ray J, Scarpino V, Laing C, Haskins ME. Biochemical basis of the beta-glucuronidase gene defect causing canine mucopolysaccharidosis VII. J Hered 90:119-123, 1999.

Silverstein Dombrowski DC, Carmichael KP, Wang P, O'Malley TM, Haskins ME, Giger U. Mucopolysaccharidosis type VII in a German Shepherd Dog. J Am Vet Med Assoc. 2004 Feb 15;224(4):553-7, 532-3.

96. Muscular Dystrophy, Ullrich-type; mutation originally found in Landseer

Disease Category Type
muscular

Description
Muscular dystrophies are a group of progressive, hereditary disorders leading to muscular dysfunction. A specific form of the disease has been described in the Landseer. Muscular dystrophy in Landseer dogs causes difficulty on ambulation and atrophied muscles in young puppies. Clinical signs progress and affected dogs are euthanized before 2 years of age due to severe muscular weakness. The mode of inheritance is autosomal recessive.

Clinical Overview
Clinical signs of the disease appear at a few weeks of age with difficulty in ambulation, short-strided gait, and atrophied muscles. Some affected puppies have severe clinical signs from birth and are euthanized in their first weeks of life. Puppies may also have difficulties swallowing, present with frequent regurgitation, or salivation. Clinical signs progress leading to severe muscle weakness before 2 years of age. The prognosis of the disease is grave.

Mutation Found In:
Landseer

Gene Variant Tested
COL6A1 Landseer

Clinical Signs
progressive muscular dysfunction

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Steffen F, Bilzer T, Brands J, Golini L, Jagannathan V, Wiedmer M, Drögemüller M, Drögemüller C, Leeb T. A nonsense variant in COL6A1 in Landseer dogs with muscular dystrophy. G3 (Bethesda). Oct 4;5(12):2611-7, 2015.

97. Muscular Hypertrophy (Double Muscling)

Disease Category Type
muscular

Description
Muscular hypertrophy, also called double muscling, is characterized by increased muscle mass. The trait is caused by a mutation in the myostatin (MSTN) gene. Myostatin regulates the size of muscles and prevents them from growing too large. The trait is encountered in the Whippet. Muscular hypertrophy is inherited as an autosomal trait.

Clinical Overview
Whippets that are homozygous for the mutation are highly over-muscled. The heavily muscled Whippets, also called "bully whippets, have broad chests and unusually well-developed leg and neck musculature. "Bully Whippets can easily be distinguished from their normal littermates based on physical appearance. Double muscled Whippets don't seem to have any health problems other than occasional muscle cramping. Carrier dogs seem to benefit from the mutation since they are known to be faster in competitive racing than normal individuals.

Mutation Found In:
Whippet

Gene Variant Tested
MSTN

Clinical Signs
increased muscle mass

Mode of Inheritance
recessive but may also affect some heterozygotes

Signs Seen in Affected Carriers
increased racing speed

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, Ostrander EA. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet 3:e79, 2007.

Shelton GD, Engvall E. Gross muscle hypertrophy in whippet dogs is caused by a mutation in the myostatin gene. Neuromuscul Disord 17:721-2, 2007.

98. Musladin-Lueke Syndrome, (MLS)

Disease Category Type
skeletal and dermal

Description
Musladin-Lueke syndrome (MLS) is a hereditary disorder affecting the development and structure of connective tissue in Beagles. MLS is a multi-systemic condition characterized by stiff joints, an abnormal facial expression, and thick, tight skin. Musladin-Lueke syndrome is inherited as an autosomal recessive trait.

Clinical Overview
Affected dogs have a broad skull, wide-set slanted eyes, and skin that appears thick and tight. The disorder is characterized by extremely limited joint mobility and short digits that causes the dogs to walk upright, often on their tip-toes. Affected dogs are smaller in size than their littermates. Other characteristics of the disorder include a high-pitched bark and an exceptionally exuberant temperament. Dogs with MLS typically have a normal life span, but commonly develop painful arthritis. The clinical signs usually stabilize by 1 year of age.

Mutation Found In:
Beagle

Gene Variant Tested
ADAMTSL2

Clinical Signs
thick tight skin, stiff joints, broad skull, and slanted eyes

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Bader HL, Ruhe AL, Wang LW, Wong AK, Walsh KF, Packer RA, Mitelman J, Robertson KR, O'Brien DP, Broman KW, Shelton GD, Apte SS, Neff MW An ADAMTSL2 founder mutation causes Musladin-Lueke Syndrome, a heritable disorder of beagle dogs, featuring stiff skin and joint contractures. PLoS One. 17;5(9) e12871, 2010.

99. Myeloperoxidase Deficiency; mutation originally found in Italian Hound

Disease Category Type
immunologic

Description
Myeloperoxidase deficiency is a rare hereditary condition characterized by decreased function or absence of the myeloperoxidase enzyme in neutrophils and monocytes. Affected dogs are usually asymptomatic but they may have increased susceptibility to fungal and bacterial infections. The disease has been reported in Italian hounds. The mode of inheritance is autosomal recessive.

Clinical Overview
Affected dogs are usually clinically normal though an increased susceptibility to infections, especially fungal and bacterial infections, has been associated with the disease. The disease might also predispose an affected dog to neoplastic and neurodegenerative changes. The disease is caused by the deficient or absent function of the myeloperoxidase enzyme in neutrophils and monocytes. Therapy is targeted at treating secondary infections.

Mutation Found In:
Italian Hound

Gene Variant Tested
MOP

Clinical Signs
susceptibility to fungal and bacterial infections

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gentilini F, Zambon E, Mancini D, Turba ME. A nonsense mutation in the myeloperoxidase gene is responsible for hereditary myeloperoxidase deficiency in an Italian hound dog. Anim Genet. 2016 Oct;47(5):632-3.

100. Myotonia Congenita; mutation originally found in Australian Cattle Dog

Disease Category Type
muscular

Description
Myotonia congenita is a congenital muscular disorder as the name suggests that affects multiple breeds. The condition causes affected dogs to have hyperexcitable muscles that contract easily. The disorder is characterized by stiff movements and delayed muscle relaxation after exercise. This particular genetic variant has been found in the Australian Cattle Dog. Myotonia congenita is inherited as an autosomal recessive trait.

Clinical Overview
Myotonia is a muscular disorder caused by a defect in ion channels of the skeletal muscles which leads to delayed relaxation of skeletal muscles following contractions. The clinical signs can be seen in puppies only a few weeks old. An affected dog suffers from muscle hypertrophy and has stiff movements. It can have difficulties rising after rest and in rapid changes of posture. The disorder is characterized by a bunny-hopping gate. An affected dog may also suffer from superior prognathism (protrusion of one or both jaws), ptyalism (excessive flow of saliva), dental abnormalities, and increased respiratory sounds during exercise. The tongue of affected dogs is enlarged and stiffens when touched.

Mutation Found In:
Australian Cattle Dog, Australian Stumpy Tail Cattle Dog

Gene Variant Tested
CLCN1 Australian Cattle Dog

Clinical Signs
delayed muscle reaction, stiff movements, hypertrophic skeletal muscles, and bunny-hop-like movement

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Bhalerao DR, Rajpurohit Y, Vite CH, Giger U. Detection of a genetic mutation for myotonia congenita among Miniature Schnauzers and identification of a common carrier ancestor. Am J Vet Res 63:1443-1447, 2002.

Rhodes TH, Vite CH, Giger U, Patterson DF, Fahlke C, George AL. A missense mutation in canine ClC-1 causes recessive myotonia congenita in the dog. FEBS Lett 456:54-58, 1999.

Vite CH, Melniczek J, Patterson D, Giger U. Congenital myotonic myopathy in the miniature schnauzer: An autosomal recessive trait. J Hered 90:578-580, 1999.

101. Narcolepsy; mutation originally found in Dachshund

Disease Category Type
neurologic

Description
Narcolepsy is a sleep disorder that causes sudden attacks of sleep due to the brain's inability to regulate REM sleep. Narcolepsy is encountered in several dog breeds. The underlying mutation has been identified in the Doberman Pinscher and Labrador Retriever, though this variant is associated with the Dachshund. Narcolepsy in dogs is associated with cataplexy (sudden loss of muscle tone without loss of consciousness). The clinical signs of narcolepsy include drowsiness and disrupted sleep patterns, and are usually observed by 6 months of age. The condition is not progressive or life-threatening. Narcolepsy is inherited in an autosomal recessive manner.

Clinical Overview
The first clinical signs of inherited narcolepsy are usually observed by 6 months of age. A typical sign of narcolepsy is excessive daytime drowsiness or decreased daytime activity compared to dogs of the same breed and age. The clinical signs of narcolepsy also include cataplexic episodes characterized by sudden loss of muscle tone. Cataplexic episodes start with the dog's hind legs bending and neck hanging down followed by a collapse which might result in the dog laying down for several seconds or minutes. An affected dog may try to resist the attack which can be seen as a wobbly gait and hind leg weakness. The dog usually stays conscious and alert especially in the beginning of the episode. However, if the attack lasts longer than a couple of minutes, the dog may fall asleep. In longer episodes, fast eye movement characteristic for REM sleep can be observed. Muscle twitches and slow repetitive muscle movements are also possible. Unlike in epileptic seizures, muscles are relaxed during cataplexic episodes and no drooling, urinating, or defecation is observed. Feeding and playing with the dog can provoke cataplexic episodes.

Mutation Found In:
Dachsund

Gene Variant Tested
HCRTR2 Dachshund

Clinical Signs
excessive daytime sleepiness or decreased activity, and cataplexy

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin XY, Qiu XH, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365-376, 1999.

Hungs M, Fan J, Lin L, Lin XY, Maki RA, Mignot E. Identification and functional analysis of mutations in the Hypocretin (Orexin) genes of narcoleptic canines. Gen Res 11:531-539, 2001.

Tonokura M, Fujita K, Nishino S. Review of pathophysiology and clinical management of narcolepsy in dogs. Vet Rec 161:375-80, 2007.

102. Narcolepsy; mutation originally found in Labrador Retriever

Disease Category Type
neurologic

Description
Narcolepsy is a sleep disorder that causes sudden attacks of sleep due to the brain's inability to regulate REM sleep. Narcolepsy is encountered in several dog breeds. The underlying mutation has been identified in the Dachshund and Doberman Pinscher though this variant is associated with the Labrador Retriever. Narcolepsy in dogs is associated with cataplexy (sudden loss of muscle tone without loss of consciousness). The clinical signs of narcolepsy include drowsiness and disrupted sleep patterns, and are usually observed by 6 months of age. The condition is not progressive or life-threatening. Narcolepsy is inherited in an autosomal recessive manner.

Clinical Overview
The first clinical signs of inherited narcolepsy are usually observed by 6 months of age. A typical sign of narcolepsy is excessive daytime drowsiness or decreased daytime activity compared to dogs of the same breed and age. The clinical signs of narcolepsy also include cataplexic episodes characterized by sudden loss of muscle tone. Cataplexic episodes start with the dog's hind legs bending and neck hanging down followed by a collapse which might result in the dog laying down for several seconds or minutes. An affected dog may try to resist the attack which can be seen as a wobbly gait and hind leg weakness. The dog usually stays conscious and alert especially in the beginning of the episode. However, if the attack lasts longer than a couple of minutes, the dog may fall asleep. In longer episodes, fast eye movement characteristic for REM sleep can be observed. Muscle twitches and slow repetitive muscle movements are also possible. Unlike in epileptic seizures, muscles are relaxed during cataplexic episodes and no drooling, urinating, or defecation is observed. Feeding and playing with the dog can provoke cataplexic episodes.

Mutation Found In:
Doberman Pinscher, Labrador Retriever, Dachsund

Gene Variant Tested
HCRTR2 Labrador Retriever

Clinical Signs
excessive daytime sleepiness or decreased activity, and cataplexy

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin XY, Qiu XH, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365-376, 1999.

Hungs M, Fan J, Lin L, Lin XY, Maki RA, Mignot E. Identification and functional analysis of mutations in the Hypocretin (Orexin) genes of narcoleptic canines. Gen Res 11:531-539, 2001.

Tonokura M, Fujita K, Nishino S. Review of pathophysiology and clinical management of narcolepsy in dogs. Vet Rec 161:375-80, 2007.

103. Nemaline Myopathy; mutation originally found in American Bulldog

Disease Category Type
muscular

Description
Nemaline myopathy is a rare muscular disorder that is characterized by nemaline rod bodies inside muscle fibers. Nemaline myopathy can be either hereditary or acquired and there are different forms of the disorder. Here we describe the rare hereditary nemaline myopathy that has been found in the American Bulldog breed. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Clinical signs are first noticed around 2 months of age. Affected puppies are able to move but have generalized muscle atrophy and tremors leading to exercise intolerance. The clinical signs are relatively non-progressive.

Mutation Found In:
American Bulldog

Gene Variant Tested
NEB

Clinical Signs
muscle weakness, exercise intolerance, and tremors

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Evans J, Cox M, Huska J, Li F, Gaitero L, Guo L, Casal M, Granzier H, Shelton D, Clark LA. Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy. Mamm Genome (2016) 27:495–502. DOI 10.1007/s00335-016-9644-9.

104. Neonatal Cerebellar Cortical Degeneration or Cerebellar Abiotrophy, (NCCD)

Disease Category Type
neurologic

Description
Neonatal cerebellar cortical degeneration or cerebellar abiotrophy (NCCD) is encountered in several dog breeds. Cerebellar abiotrophy is characterized by progressive degeneration of neurons in the cerebellar cortex. An affected dog suffers from ataxia (uncoordinated movements) and dysmetria (improper measuring of distance in muscular acts). The age of onset and the progression of clinical signs seem to vary in different breeds due to different causative mutations. This variant is found in the Beagle and is inherited as an autosomal recessive condition.

Clinical Overview
The typical signs of neonatal cerebellar cortical degeneration (NCCD) in Beagles can be seen when affected puppies start to move at three weeks of age. The clinical signs include cerebellar ataxia, wide-based stance, loss of balance, and dysmetric gait with inability to regulate rate and range of movement. The affected puppies have a normal state of alertness.

Mutation Found In:
Beagle

Gene Variant Tested
SPTBN2

Clinical Signs
loss of coordination of movement and loss of balance

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Forman OP, De Risio L, Stewart J, Mellersh CS, Beltran E. Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation. BMC Genet 13:55, 2012.

Kent M, Glass E, de Lahunta A. Cerebellar cortical abiotrophy in a beagle. J Small Anim Pract 41(7):321-323, 2000.

105. Neonatal Encephalopathy with Seizures, (NEWS)

Disease Category Type
neurologic

Description
Neonatal encephalopathy with seizures (NEWS) is an inherited disorder encountered in the Standard Poodle that affects the development and structure of the cerebellum. The life expectancy of affected dogs is less than seven weeks. NEWS is inherited in an autosomal recessive manner.

Clinical Overview
Puppies suffering from NEWS are smaller and weaker at birth than their littermates and they often have difficulties nursing. Most of the affected puppies won't make it through the first week of their life. Puppies that survive past the first week suffer from ataxia (uncoordinated movements), whole-body tremor and weakness progressing to severe generalized clonic-tonic seizures by 4-6 weeks of age. No affected puppies have survived past 7 weeks of age and they are often euthanized earlier.

Mutation Found In:
Standard Poodle

Gene Variant Tested
ATF2

Clinical Signs
ataxia, muscle weakness, difficulties nursing, generalized seizures, and death

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Chen X, Johnson GS, Schnabel RD, Taylor JF, Johnson GC, Parker HG, Patterson EE, Katz ML, Awano T, Khan S, O'Brien DP. A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. Neurogenetics 9(1):41-49, 2008.

106. Neuroaxonal Dystrophy; mutation originally found in Spanish Water Dog

Disease Category Type
neurologic

Description
Neuroaxonal dystrophy in Spanish Water Dogs is a rare neurodegenerative disorder. Clinical signs appear between six and eleven months of age. Affected dogs are presented with progressing neurological signs such as gait abnormalities, abnormal vocalization, incontinence, and behavioral changes. The disease is pathologically characterized by spheroid formation in the central nervous system. The inheritance pattern is autosomal recessive. Clinical signs are progressive and usually result in euthanasia over quality of life concerns.

Clinical Overview
Clinical signs of the disease are progressive in nature and include gait abnormalities; behavioral changes such as dullness, nervousness, or abnormal vocalization; incontinence; and uncontrolled defecation. Affected dogs may also show compulsory pacing, visual deficits, nystagmus, tilting of the head and neurological deficits, predominantly related to sensory localization. Neurological examination may show a mild head tilt, generalized cerebellar ataxia, hypermetria of the thoracic limbs, a depressed patellar reflex, proprioceptive deficits, decreased menace, visual deficits, positional nystagmus, and decreased muscle tone. Due to the progressive nature of the condition, clinical signs typically lead to euthanasia before two years of age. A characteristic pathologic feature for the disease is the development of spheroids in the central nervous system. Spheroid formation can be observed in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem, and in the sensory pathways of the spinal cord.

Mutation Found In:
Spanish Water Dog

Gene Variant Tested
TECPR2 Spanish Water Dog

Clinical Signs
progressive neurological signs, gait abnormalities, behavioral deficits, incontinence

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Hahn K, Rohdin C, Jagannathan V, Wohlsein P, Baumgärtner W, Seehusen F, Spitzbarth I, Grandon R, Drögemüller C, Jäderlund K. TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs. PLoS ONE 10(11): e0141824, 2015.

107. Neuronal Ceroid Lipofuscinosis 1, (NCL1); mutation originally found in Dachshund

Disease Category Type
neurologic

Description
Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive neurodegenerative lysosomal storage disorders. Neuronal ceroid lipofuscinoses are characterized by excessive accumulation of lipofuscin and ceroid lipopigments in the central nervous system and other tissues. Different forms of NCLs differ by age of onset and pattern of progression. Usually progressive loss of vision is the first observable sign. In addition, the clinical signs of NCLs include ataxia (uncoordinated movements), seizures, and behavioral changes, such as aggression. Type 1 form of NCL is encountered in Dachshunds. The onset of clinical signs is usually by 9 months of age. NCL1 is inherited in an autosomal recessive manner.

Clinical Overview
Type 1 form of neuronal ceroid lipofuscinosis is similar to type 2 in terms of clinical signs and age of onset. The first clinical signs of NCL type 1 can be seen before one year of age. NCL type 1 is a progressive condition characterized by rapidly progressing vision impairment, ataxia (uncontrolled movements), and behavioral changes, such as anxiety, sound sensitivity, and inability to recognize familiar individuals. Clinical signs of NCL1 also include general weakness and uncontrolled rhythmic head movements.

Mutation Found In:
Dachshund

Gene Variant Tested
PPT1

Clinical Signs
vision impairment, ataxia, behavioral changes, and seizures

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Sanders DN, Farias FH, Johnson GS, Chiang V, Cook JR, O'Brien DP, Hofmann SL, Lu JY, Katz ML. A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Mol Genet Metab 100(4):349-56, 2010.

108. Neuronal Ceroid Lipofuscinosis 7, (NCL7); mutation originally found in Chinese Crested Dog and Chihuahua

Disease Category Type
neurologic

Description
Neuronal ceroid lipofuscinoses are a group of rare heritable lysosomal storage diseases that cause progressive neurological dysfunction. Clinical signs may start with compulsory behavior signs and develop into impairment of vision and degeneration of cognitive and motor skills. A causative mutation for NCL7 has been found in Chinese Crested dogs and the Chihuahua. The mode of inheritance is autosomal recessive.

Clinical Overview
The disease causes progressive neurological signs caused by the accumulation of storage granules in neurons and other cell types. Affected dogs seem normal as puppies but develop progressive neurological signs around one year of age. First signs of the disease include exhibiting forms of compulsory behavior, such as excessive licking of a body part. As the disease progresses, affected dogs show further changes in behavior and develop motor and vision impairment. Affected dogs may be progressively more fearful and hyper-responsive to stimuli. Affected dogs may also develop epileptic seizures in later stages.

Mutation Found In:
Chinese Crested, Chihuahua

Gene Variant Tested
MFSD8

Clinical Signs
progressive neurological signs, blindness, cognitive impairment, motor impairment

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Guo J, O'Brien D, Mhlanga-Mutangadura T, Olby N, Taylor J, Schnabel R, Katz M, Johnson G. A rare homozygous MFSD8 single-base-pair deletion and frameshift in the whole genome sequence of a Chinese Crested dog with neuronal ceroid lipofuscinosis. BMC Vet Res;10:960, 2015.

109. Neuronal Ceroid Lipofuscinosis 8, (NCL8); mutation originally found in Alpine Dachsbracke

Disease Category Type
neurologic

Description
Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive neurodegenerative lysosomal storage disorders. Neuronal ceroid lipofuscinoses are characterized by excessive accumulation of lipofuscin and ceroid lipopigments in the central nervous system and other tissues. Different forms of NCLs differ by age of onset and pattern of progression. Usually progressive loss of vision is the first observable sign. In addition, the clinical signs of NCLs include ataxia (uncoordinated movements), seizures, and behavioral changes, such as aggression. Causative mutations for NCL type 8 have been found in English Setters, Australian Shepherds, and Alpine Dachsbracke. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
The first signs of NCL8 are usually observed at the age of 1-2 years. The clinical signs include ataxia (uncoordinated movements), behavioral changes, vision loss, and epileptic seizures. NCL8 is a progressive condition. The lifespan of affected dogs is rarely over two years of age due to severity of the clinical signs.

Mutation Found In:
Alpine Dachsbracke

Gene Variant Tested
CLN8 Alpine Dachsbracke

Clinical Signs
ataxia, hypermetria, and paraparesis

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Guo J, Johnson GS, Brown HA, Provencher ML, da Costa RC, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, O'Brien DP, Katz ML. A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry. Mol Genet Metab 112:302-9, 2014.

Katz ML, Khan S, Awano T, Shahid SA, Siakotos AN, Johnson GS. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun 327:541-7, 2005.

Lingaas F, Aarskaug T, Sletten M, Bjerk's I, Grimholt U, Moe L, Juneja RK, Wilton AN, Galibert F, Holmes NG, Dolf G. Genetic markers linked to neuronal ceroid lipofuscinosis in English setter dogs. Anim Genet 1998;29:371-376.

110. Neuronal Ceroid Lipofuscinosis 8, (NCL8); mutation originally found in Australian Shepherd

Disease Category Type
neurologic

Description
Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive neurodegenerative lysosomal storage disorders. Neuronal ceroid lipofuscinoses are characterized by excessive accumulation of lipofuscin and ceroid lipopigments in the central nervous system and other tissues. Different forms of NCLs differ by age of onset and pattern of progression. Usually progressive loss of vision is the first observable sign. In addition, the clinical signs of NCLs include ataxia (uncoordinated movements), seizures, and behavioral changes, such as aggression. NCL type 8 is encountered in English Setters, though this particular variant has been described in the Australian Shepherd. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
The first signs of NCL8 are usually observed at the age of 1-2 years. The clinical signs include ataxia (uncoordinated movements), behavioral changes, vision loss, and epileptic seizures. NCL8 is a progressive condition. The lifespan of affected dogs is rarely over two years of age due to severity of the clinical signs.

Mutation Found In:
Australian Shepherd, Australian Cattle Dog, Miniature American Shepherd

Gene Variant Tested
CLN8 Australian Shepherd

Clinical Signs
ataxia, hypermetria, and paraparesis

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Guo J, Johnson GS, Brown HA, Provencher ML, da Costa RC, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, O'Brien DP, Katz ML. A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry. Mol Genet Metab 112:302-9, 2014.

Katz ML, Khan S, Awano T, Shahid SA, Siakotos AN, Johnson GS. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun 327:541-7, 2005.

Lingaas F, Aarskaug T, Sletten M, Bjerk's I, Grimholt U, Moe L, Juneja RK, Wilton AN, Galibert F, Holmes NG, Dolf G. Genetic markers linked to neuronal ceroid lipofuscinosis in English setter dogs. Anim Genet 1998;29:371-376.

111. Neuronal Ceroid Lipofuscinosis 8, (NCL8); mutation originally found in English Setter

Disease Category Type
neurologic

Description
Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive neurodegenerative lysosomal storage disorders. Neuronal ceroid lipofuscinoses are characterized by excessive accumulation of lipofuscin and ceroid lipopigments in the central nervous system and other tissues. Different forms of NCLs differ by age of onset and pattern of progression. Usually progressive loss of vision is the first observable sign. In addition, the clinical signs of NCLs include ataxia (uncoordinated movements), seizures, and behavioral changes, such as aggression. NCL type 8 is encountered in English Setters, but a rare case of a similar mutation has also been described in the Australian Shepherd. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
The first signs of NCL8 are usually observed at the age of 1-2 years. The clinical signs include ataxia (uncoordinated movements), behavioral changes, vision loss, and epileptic seizures. NCL8 is a progressive condition. The lifespan of affected dogs is rarely over two years of age due to severity of the clinical signs.

Mutation Found In:
English Setter

Gene Variant Tested
CLN8 English Setter

Clinical Signs
blindness, anxiety, sensitivity to touch and sound, and ataxia

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Guo J, Johnson GS, Brown HA, Provencher ML, da Costa RC, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, O'Brien DP, Katz ML. A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry. Mol Genet Metab 112:302-9, 2014.

Katz ML, Khan S, Awano T, Shahid SA, Siakotos AN, Johnson GS. A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun 327:541-7, 2005.

Lingaas F, Aarskaug T, Sletten M, Bjerk's I, Grimholt U, Moe L, Juneja RK, Wilton AN, Galibert F, Holmes NG, Dolf G. Genetic markers linked to neuronal ceroid lipofuscinosis in English setter dogs. Anim Genet 1998;29:371-376.

112. Osteochondrodysplasia; mutation originally found in Miniature Poodle

Disease Category Type
skeletal

Description
Osteochondrodysplasias are inherited disorders of bone and cartilage development. Miniature Poodles suffer from an early-onset form of osteochondrodysplasia characterized by stunted growth, misshapen limbs, and abnormal movement. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
The clinical signs of osteochondrodysplasia in Miniature Poodles include a flattened ribcage, deformed paws, abducted hind limbs, enlarged joints, and an underbite. Long bones of the limbs are shortened and bent. Affected dogs are smaller in size compared to their unaffected littermates. The signs of osteochondrodysplasia can typically be observed in puppies as young as 3 weeks of age. Affected dogs can live for several years, but they often suffer from arthritis caused by misshapen limbs. Abnormal structure of the ribcage can cause breathing difficulties.

Mutation Found In:
Miniature Poodle

Gene Variant Tested
SLC13A1

Clinical Signs
stunted growth, misshapen limbs, abnormal movement, abducted hind limbs, enlarged joints, flattened rib cage, shortened and bent long bones, deformed paws, and underbite

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Jackson GC, Mittaz-Crettol L, Taylor JA, Mortier GR, Spranger J, Zabel B, Le Merrer M, Cormier-Daire V, Hall CM, Offiah A, Wright MJ, Savarirayan R, Nishimura G, Ramsden SC, Elles R, Bonafe L, Superti-Furga A, Unger S, Zankl A, Briggs MD. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat 33:144-57, 2012.

Neff MW, Beck JS, Koeman JM, Boguslawski E, Kefene L, Borgman A, Ruhe AL. Partial Deletion of the Sulfate Transporter SLC13A1 Is Associated with an Osteochondrodysplasia in the Miniature Poodle Breed. PLoS One 7:e51917, 2012.

113. Osteogenesis Imperfecta, (OI); mutation originally found in Beagle

Disease Category Type
skeletal

Description
Osteogenesis imperfecta (OI) is a severe inherited skeletal disorder encountered in multiple dog breeds, though this mutation was first identified in the Beagle. Osteogenesis imperfecta is characterized by defective collagen resulting in fragile bones and loose joints. The disorder is inherited in an autosomal dominant manner.

Clinical Overview
The clinical signs of osteogenesis imperfecta include brittle bones, joint laxity, and brittle, opalescent teeth. Other possible signs are loss of hearing, stunted growth, and blue tinted sclera. The clinical signs are already evident in puppyhood. Bones of affected dogs fracture easily, for example during the course of normal puppy play.

Mutation Found In:
Beagle

Gene Variant Tested
COL1A2 Beagle

Clinical Signs
bones that break easily, weak teeth, dentinogenesis imperfecta, and hyperlaxity

Mode of Inheritance
autosomal dominant

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Campbell BG, Wootton JAM, Macleod JN, Minor RR. Canine COL1A2 mutation resulting in C-terminal truncation of pro-alpha 2(I) and severe osteogenesis imperfecta. Journal of Bone & Mineral Research16:1147-1153, 2001.

114. Osteogenesis Imperfecta, (OI); mutation originally found in Dachshund

Disease Category Type
skeletal

Description
Osteogenesis imperfecta (OI) is a severe skeletal disorder that affects multiple breeds, though the mutation was originally found in the Dachshund, where it is known as Brittle Bone Disease. This disease results in defective collagen, which causes fragile bones and hyperlaxity. Osteogenesis imperfecta is inherited in an autosomal recessive manner.

Clinical Overview
Clinical signs of OI include bones that break easily, hyperlaxity of joints, and weak or underdeveloped, slightly pink teeth. Other possible signs are impaired hearing, dwarfism, and bluish tint of sclera. Clinical signs are already visible at a young age. Bones can break very easily; for example, normal puppy play can result in fractures.

Mutation Found In:
Dachshund

Gene Variant Tested
SERPINH1

Clinical Signs
bones that break easily, weak teeth, dentinogenesis imperfect, and hyperlaxity

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Drögemüller C, Becker D, Brunner A, Haase B, Kircher P, Seeliger F, Fehr M, Baumann U, Lindblad-Toh K, Leeb T. A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta. PLoS Genet 5:e1000579, 2009.

Eckardt J, Kluth S, Dierks C, Philipp U, Distl O. Population screening for the mutation associated with osteogenesis imperfecta in dachshunds. Vet Rec: 1, 2013.

Schutz E, Drögemüller C, Scharfenstein M, Brenig B. Osteogenesis imperfect in the Dachshund. Kleintierpraxis 57:57-62, 2012.

115. Paroxysmal Dyskinesia, (PxD); mutation originally found in Soft Coated Wheaten Terrier

Disease Category Type
neurologic

Description
Paroxysmal dyskinesia is a rare hereditary neurological disorder. The disorder causes episodes of abnormal tone or movement of limbs. Affected dogs seem normal between these episodes. No abnormalities are seen in the MRI or postmortem examination of the brain. The inheritance pattern is autosomal recessive.

Clinical Overview
Clinical signs emerge between 8 months and 3 years of age with a median of 2 1/4 years. The disorder causes episodes of flexion and extension of the hind limbs. Mild episodes can be seen as exaggerated flexion of one hind limb while walking or as a stiff gait. Severe episodes can include the front legs and the dog may be unable to walk or stand. Affected dogs are conscious during these episodes. An episode could last as little as several minutes up to over four hours. Frequency can vary as well: from once every few days to over ten times a day. Affected dogs seem normal between these episodes. The severity of these episodes tends to increase over time.

Mutation Found In:
Soft Coated Wheaten Terrier

Gene Variant Tested
PIGN

Clinical Signs
episodes of abnormal tone or movement of limbs

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kolicheski A, Johnson G, Mhlanga-Mutangadura T, Taylor J, Schnabel R, Kinoshita T, Murakami Y, O’Brien D. A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia. Neurogenetics (2017) 18:39. https://doi.org/10.1007/s10048-016-0502-4

116. Persistent Müllerian Duct Syndrome, (PMDS); mutation originally found in Miniature Schnauzer

Disease Category Type
reproductive

Description
Persistent Müllerian duct syndrome (PMDS, pseudohermaphroditism) is a disorder of sexual development affecting male Miniature Schnauzers. PMDS is characterized by Müllerian duct derivatives (e.g., uterus) developing in otherwise externally normal-appearing males. The condition is inherited in a sex-limited, autosomal recessive manner, i.e., the disease only manifests in males.

Clinical Overview
The males affected with PMDS appear externally normal, but they have a uterus, cervix, part of the vagina, and fallopian tubes. Approximately 50% of PMDS-affected males are cryptorchid (absence of one or both testes from the scrotum). PMDS is characterized by sterility or subfertility, but affected males that are unilateral cryptorchids have sired litters. Aged PMDS dogs may develop pyometra (uterine infection) or a Sertoli cell tumor.

Mutation Found In:
Miniature Schnauzer

Gene Variant Tested
AMHR2

Clinical Signs
internal female reproductive organs in externally normal males, cryptorchidism, sterility or subfertility, uterine infections, and Sertoli cell tumor

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wu X, Wan S, Pujar S, Haskins ME, Schlafer DH, Lee MM, Meyers-Wallen VN. A single base pair mutation encoding a premature stop codon in the MIS type II receptor is responsible for canine persistent Müllerian duct syndrome. J Androl. 30(1):46-56, 2009.

117. Phosphofructokinase (PFK) Deficiency or Glycogen Storage Disease Type VII

Disease Category Type
blood

Description
Phosphofructokinase (PFK) is an enzyme that is crucial for production of energy from sugar sources in all cells of the body, especially red blood cells and muscle cells. Lack of this enzyme causes exertional myopathy and hemolysis resulting in a range of effects including weakness and muscle cramps, discolored urine, anemia, and jaundice. Hereditary (PFK) deficiency affects mainly spaniel and mixed breed dogs. The disorder follows an autosomal recessive mode of inheritance.

Clinical Overview
Dogs suffering from PFK deficiency display hemolytic anemia (breakdown of red blood cells) especially with alkaline blood. Barking or panting, rigorous exercising, or high environmental temperature may trigger the clinical signs by increasing the body's pH value. This may lead to a hemolytic crisis causing anemia, fatigue, and fever. The urine of an affected dog may become dark brown and their skin may turn yellow following the episode. Other milder clinical signs include muscle weakness and reduced exercise tolerance. Cardiac problems have also been observed in Whippets.

Mutation Found In:
American Cocker Spaniel, English Cocker Spaniel, English Springer Spaniel, Whippet

Gene Variant Tested
PFKM

Clinical Signs
hemolytic anemia, hemolytic crises, mild metabolic myopathy, pigmenturia, as well as cardiac problems (observed in the Whippet only)

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gerber K, Harvey JW, D'Agorne S, Wood J, Giger U. Hemolysis, myopathy, and cardiac disease associated with hereditary phosphofructokinase deficiency in two Whippets. Vet Clin Pathol 38(1):46-51, 2009.

Giger U, Harvey JW, Yamaguchi RA, McNulty PK, Chiapella A, Beutler E. Inherited phosphofructokinase deficiency in dogs with hyperventilation-induced hemolysis: increased in vitro and in vivo alkaline fragility of erythrocytes. Blood 65(2):345-51, 1985.

Hillström A, Tvedten H, Rowe A, Giger U. Hereditary phosphofructokinase deficiency in wachtelhunds. J Am Anim Hosp Assoc 47(2):145-50, 2011.

Inal Gultekin G, Raj K, Lehman S, Hillström A, Giger U. Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog. Mol Cell Probes 26(6):243-247, 2012.

Smith BF, Stedman H, Rajpurohit Y, Henthorn PS, Wolfe JH, Patterson DF, Giger U. Molecular basis of canine muscle type phosphofructokinase deficiency. J BiolChem 16:271(33):20070-20074, 1996.

Vora S, Giger U, Turchen S, Harvey JW. Characterization of the enzymatic lesion in inherited phosphofructokinase deficiency in the dog: an animal analogue of human glycogen storage disease type VII. Proc Natl Acad Sci U S A 82(23):8109-8113, 1985. br>

118. Polycystic Kidney Disease, (PKD); mutation originally found in Bull Terrier

Disease Category Type
renal

Description
Polycystic kidney disease (PKD) in Bull Terriers is an inherited kidney disease affecting English Bull Terriers. Affected dogs develop bilateral kidney cysts. PKD is inherited in an autosomal dominant manner.

Clinical Overview
In PKD, an affected dog develops several bilateral kidney cysts of different sizes, which cause structural kidney damage. The disease leads to chronic renal failure in adulthood. Clinical signs of chronic renal failure include excessive drinking and frequent urination.

Mutation Found In:
Bull Terrier

Gene Variant Tested
PKD1

Clinical Signs
bilateral renal cysts and renal failure

Mode of Inheritance
autosomal dominant

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gharahkhani P, O'Leary CA, Kyaw-Tanner M, Sturm RA, Duffy DL. A non-synonymous mutation in the canine Pkd1 gene is associated with autosomal dominant polycystic kidney disease in Bull Terriers. PLoS ONE6:e22455, 2011.

119. Prekallikrein Deficiency

Disease Category Type
blood

Description
Prekallikrein deficiency is a rare inherited disorder characterized by increased blood clotting time. The causative mutation for prekallikrein deficiency has been identified in the Shih Tzu breed. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Prekallikrein is a plasma protein required for blood clotting. Prekallikrein deficiency can cause prolonged clotting time in case of injury. The disorder is not usually associated with spontaneous bleeding. There is no treatment available for prekallikrein deficiency but usually affected dogs present no clinical signs under normal circumstances and have a normal lifespan. However, prekallikrein deficiency should be taken into account in case of surgery or trauma.

Mutation Found In:
Shih Tzu

Gene Variant Tested
KLKB1

Clinical Signs
prolonged blood clotting time

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Okawa T, Yanase T, Shimokawa Miyama T, Hiraoka H, Baba K, Tani K, Okuda M, Mizuno T. Prekallikrein Deficiency in a Dog. J Vet Med Sci, 2010.

120. Primary Ciliary Dyskinesia, (PCD)

Disease Category Type
other

Description
Primary ciliary dyskinesia (PCD) is a disorder found to affect ciliary formation in multiple breeds, causing recurrent respiratory tract inflammations and infertility in males. PCD is inherited in an autosomal recessive manner.

Clinical Overview
Cilia of the body are found in the respiratory tract, genitourinary system, and middle ear. Cilia in the lungs work to keep the airways clear by propelling mucus and dirt onward in the respiratory tract. Abnormal cilia function causes respiratory tract inflammation such as pneumonia. The clinical signs of PCD also include infertility caused by inadequate cilia function in the sperm and oviduct. Hearing difficulties can occur as well. If primary ciliary dyskinesia is associated with situs inversus (mirrored internal organs), the condition is called Kartagener syndrome. When situs inversus occurs, the heart for example, is located on the right side of the chest.

Mutation Found In:
Old English Sheepdog

Gene Variant Tested
CCDC39

Clinical Signs
respiratory tract inflammations, infertility in males, and situs inversus or heterotaxy

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Merveille AC, Davis EE, Becker-Heck A, Legendre M, Amirav I, Bataille G, Belmont J, Beydon N, Billen F, Clément A, Clercx C, Coste A, Crosbie R, de Blic J, Deleuze S, Duquesnoy P, Escalier D, Escudier E, Fliegauf M, Horvath J, Hill K, Jorissen M, Just J, Kispert A, Lathrop M, Loges NT, Marthin JK, Momozawa Y, Montantin G, Nielsen KG, Olbrich H, Papon JF, Rayet I, Roger G, Schmidts M, Tenreiro H, Towbin JA, Zelenika D, Zentgraf H, Georges M, Lequarré AS, Katsanis N, Omran H, Amselem S. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet 43(1):72-78, 2011.

121. Primary Lens Luxation, (PLL)

Disease Category Type
ocular

Description
Primary lens luxation (PLL) is an inherited condition in dogs that can cause displacement of the ocular lenses. The disorder is caused by degeneration of the zonular fibers that are required for attachment of the lens. When the lens luxates, it may do so either anteriorly or posteriorly. PLL most closely follows an autosomal recessive mode of inheritance though heterozygous dogs also have a low risk of developing PLL.

Clinical Overview
PLL is most commonly observed in dogs 3 to 8 years of age. Subluxation, where the lens is partly detached, commonly occurs before complete luxation. An anterior lens luxation is particularly serious and manifests as squinting, redness, and watering of the eyes, requiring immediate veterinary care. Untreated, PLL results in glaucoma, corneal opacities, corneal edema, and blindness. The second lens tends to become displaced within weeks or months of the first luxation and therefore should be carefully monitored.

Mutation Found In:
American Hairless Terrier, Australian Cattle Dog, Chinese Crested Dog, Danish-Swedish Farmdog, Fox Terrier - Wire, German Hunting Terrier, Jack Russell Terrier, Lakeland Terrier, Lancashire Heeler, Miniature Bull Terrier, Mixed breed, Norwich Terrier, Parson Russell Terrier, Patterdale Terrier, Pumi, Rat Terrier, Russell Terrier, Sealyham Terrier, Tenterfield Terrier, Tibetan Terrier, Toy Fox Terrier, Volpino Italiano, Welsh Terrier, Yorkshire Terrier

Gene Variant Tested
ADAMTS17

Clinical Signs
subluxation and luxation of the lens, iridodonesis, and blindness

Mode of Inheritance
recessive but may also affect some heterozygotes

Signs Seen in Affected Carriers
a luxated lens

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Farias FH, Johnson GS, Taylor JF, Giuliano E, Katz ML, Sanders DN, Schnabel RD, McKay SD, Khan S, Gharahkhani P, O'Leary CA, Pettitt L, Forman OP, Boursnell M, McLaughlin B, Ahonen S, Lohi H, Hernandez-Merino E, Gould DJ, Sargan DR, Mellersh C. An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Invest Ophthalmol Vis Sci. 51(9):4716-4721, 2010.

Pettitt GD, McLaughlin L, Holmes B, Forman N, Thomas O, Ahonen A, Lohi S, O'Leary H, Sargan C, Cathryn DM. ADAMTS17 mutation associated with primary lens luxation is widespread among breeds. Vet Ophthalmol. 14(6):378-384, 2011.

122. Primary Open Angle Glaucoma, (POAG); mutation originally found in Basset Fauve de Bretagne

Disease Category Type
ocular

Description
Glaucoma is one of the most common ocular disorders causing irreversible blindness in dogs. Glaucoma is characterized by defects in the normal flow of intraocular fluid leading to elevated intraocular pressure which can in turn damage the optic nerve and retina. This condition leads to blindness if it is left untreated. Glaucoma affects multiple breeds but in most cases the causative mutation has not been identified. This causative mutation first identified in the Basset Fauve de Bretagne is inherited in an autosomal recessive manner.

Clinical Overview
The loss of vision from glaucoma often occurs gradually over a long period of time and the first clinical signs frequently go unnoticed. Glaucoma is usually diagnosed when intraocular pressure has been elevated enough to cause loss of vision and pain. The clinical signs include pupil dilation, redness in the eye, corneal opacification, mild enlargement of the eye, possible partial lens luxation, and abnormalities in the optic nerve and retina. Glaucoma typically affects both eyes but not necessarily simultaneously. The age of onset is typically in middle-age.

Mutation Found In:
Basset Fauve de Bretagne

Gene Variant Tested
ADAMTS17 Basset Fauve de Bretagne

Clinical Signs
increased intraocular pressure, squinting, bulging ocular globe, loss of optic nerve cells, loss of vision, and ocular pain and light sensitivity

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Forman OP, Pettitt L, Komáromy AM, Bedford P, Mellersh C. A Novel Genome-Wide Association Study Approach Using Genotyping by Exome Sequencing Leads to the Identification of a Primary Open Angle Glaucoma Associated Inversion Disrupting ADAMTS17. PLoS One. 2015 Dec 18;10(12):e0143546. doi: 10.1371/journal.pone.0143546. eCollection 2015.

Oliver JA, Forman OP, Pettitt L, Mellersh CS.Two Independent Mutations in ADAMTS17 Are Associated with Primary Open Angle Glaucoma in the Basset Hound and Basset Fauve de Bretagne Breeds of Dog. PLoS One. 2015 Oct 16;10(10):e0140436. doi: 10.1371/journal.pone.0140436. eCollection 2015.

123. Primary Open Angle Glaucoma, (POAG); mutation originally found in Petit Basset Griffon Vendeen

Disease Category Type
ocular

Description
Glaucoma is one of the most common ocular disorders causing irreversible blindness in dogs. Glaucoma is characterized by defects in the normal flow of intraocular fluid leading to elevated intraocular pressure which can in turn damage the optic nerve and retina. This condition leads to blindness if it is left untreated. Glaucoma affects multiple breeds but in most cases the causative mutation has not been identified. This causative mutation first identified in the Petit Basset Griffon Vendeen is inherited in an autosomal recessive manner.

Clinical Overview
The loss of vision from glaucoma often occurs gradually over a long period of time and the first clinical signs frequently go unnoticed. Glaucoma is usually diagnosed when intraocular pressure has been elevated enough to cause loss of vision and pain. The clinical signs include pupil dilation, redness in the eye, corneal opacification, mild enlargement of the eye, possible partial lens luxation, and abnormalities in the optic nerve and retina. Glaucoma typically affects both eyes but not necessarily simultaneously. The age of onset is typically in middle-age.

Mutation Found In:
Petit Basset Griffon Vendeen

Gene Variant Tested
ADAMTS17 PBGV

Clinical Signs
increased intraocular pressure, squinting, bulging ocular globe, loss of optic nerve cells, loss of vision, and ocular pain and light sensitivity

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Forman OP, Pettitt L, Komáromy AM, Bedford P, Mellersh C. A Novel Genome-Wide Association Study Approach Using Genotyping by Exome Sequencing Leads to the Identification of a Primary Open Angle Glaucoma Associated Inversion Disrupting ADAMTS17. PLoS One. 2015 Dec 18;10(12):e0143546. doi: 10.1371/journal.pone.0143546. eCollection 2015.

Oliver JA, Forman OP, Pettitt L, Mellersh CS.Two Independent Mutations in ADAMTS17 Are Associated with Primary Open Angle Glaucoma in the Basset Hound and Basset Fauve de Bretagne Breeds of Dog. PLoS One. 2015 Oct 16;10(10):e0140436. doi: 10.1371/journal.pone.0140436. eCollection 2015.

124. Progressive Early-Onset Cerebellar Ataxia; mutation originally found in Finnish Hound

Disease Category Type
neurologic

Description
Progressive early-onset cerebellar ataxia is a congenital neurological disorder characterized by degeneration of cerebellar nerve cells. Neuronal degeneration causes ataxia (uncoordinated movements) and loss of balance. The mutation was originally discovered in the Finnish Hound. Progressive early-onset cerebellar ataxia is inherited in an autosomal recessive manner, and affected puppies are often euthanized within a month of the onset of symptoms.

Clinical Overview
Progressive early-onset cerebellar ataxia is a rapidly progressing condition. Clinical signs are present by 3 months of age. These include generalized cerebellar ataxia, tremors, and failure to thrive. Cerebellar shrinkage is detectable through MRI. Due to the fast disease progression, euthanasia is usually elected within 1 month of onset. If performed, pathological and histological examinations yield evidence of cerebellum-restricted neurodegeneration with marked loss of Purkinje cells in the cerebellar cortex and secondary changes in other cortical layers.

Mutation Found In:
Finnish Hound

Gene Variant Tested
SEL1L

Clinical Signs
ataxia, tremors, failure to thrive

Mode of Inheritance
recessive but may also affect some heterozygotes

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kyöstilä K, Cizinauskas S, Seppälä EH, Suhonen E, Jeserevics J, Sukura A, Syrjä P, Lohi H. A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. PLoS Genet. 2012;8(6):e1002759.

125. Progressive Retinal Atrophy Type III, (PRA type III); mutation originally found in Tibetan Spaniel and Tibetan Terrier

Disease Category Type
ocular

Description
Progressive retinal atrophy (PRA) comprises a group of genetically inherited diseases affecting dogs of various breeds. PRA is characterized by retinal degeneration and progressive loss of vision culminating in blindness. PRA is known to affect over 100 breeds. Causative gene mutations have been identified in several breeds but some of them are still unidentified. PRA type III is encountered in the Tibetan Spaniel and the Tibetan Terrier. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
The onset of clinical signs of PRA type III is typically at 5 years of age with initial loss of vision in dim light (night blindness) which gradually progresses to total blindness. The first signs are caused by loss of rod photoreceptor cells required for vision in dim light followed by reduction of the visual field and blindness as the cone cells of the retina also degenerate.

Mutation Found In:
Tibetan Spaniel, Tibetan Terrier

Gene Variant Tested
FAM161A

Clinical Signs
progressive retinal degeneration, vision impairment, and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Downs LM, Mellersh CS. An Intronic SINE Insertion in FAM161A that Causes Exon-Skipping Is Associated with Progressive Retinal Atrophy in Tibetan Spaniels and Tibetan Terriers. PLoS ONE 9(4): e93990 2014.

126. Progressive Retinal Atrophy, (CNGA1-PRA); mutation originally found in Shetland Sheepdog

Disease Category Type
ocular

Description
Progressive retinal atrophy (PRA) is the common name for a family of hereditary retinal dystrophies commonly leading to blindness. PRA is found in more than 100 dog breeds. The genetic background varies highly among breeds and populations. In Shetland Sheepdogs, Collie Eye Anomaly may cause PRA but another causative mutation for PRA has been found as well. All dogs homozygous for the CNGA1 mutation have PRA but not all PRA cases in Shetland Sheepdogs can be explained by this mutation. The mode of inheritance is autosomal recessive.

Clinical Overview
Progressive retinal atrophy is a progressive, hereditary retinal degeneration. The disease is caused by degeneration of the photoreceptors which eventually leads to blindness. Usually both eyes are equally affected. Clinical signs of the disease typically appear only when the vision of the dog is already impaired. The dog may be reluctant to walk in a dark environment or up or downhill. Affected dogs may also have dilated pupils with an abnormal shine. The disease does not cause pain and there is no curative therapy. The age of onset and age of diagnosis vary between 2-11 years of age, and the inheritance pattern is autosomal recessive.

Mutation Found In:
Shetland Sheepdog

Gene Variant Tested
CNGA1

Clinical Signs
retinal degeneration, loss of vision

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Wiik A, Ropstad E, Ekesten B, Karlstam L, Wade C, Lingaas F. Progressive retinal atrophy in Shetland sheepdog is associated with a mutation in the CNGA1 gene. Anim Genet. Oct;46(5):515-21, 2015.

127. Progressive Retinal Atrophy, (PAP1_PRA); mutation originally found in Papillon and Phalène

Disease Category Type
ocular

Description
Progressive retinal atrophy (PRA) comprises a group of genetically inherited diseases affecting dogs of various breeds. PRA is characterized by retinal degeneration and progressive loss of vision culminating in blindness. PRA is known to affect over 100 breeds. Causative gene mutations have been identified in several breeds, but some of them are still unidentified. PRA affecting the Papillon and Phalène breeds is caused by a mutation in the CNGB1 gene. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
In the Papillon and Phalène breeds, the onset of clinical signs of PRA is typically at 5-6 years of age with initial loss of vision in dim light (night blindness) that gradually progresses to total blindness. The onset of clinical signs is caused by loss of rod photoreceptor cell function, followed by degeneration of cone cells. PRA in the Papillon and Phalène progresses slowly and the affected dogs often maintain adequate daylight vision throughout their natural lifespan.

Mutation Found In:
Papillon, Phalène

Gene Variant Tested
CNGB1

Clinical Signs
degeneration of the, photoreceptor cells of the retina, vision loss, and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Ahonen SJ, Arumilli M, Lohi H. A CNGB1 Frameshift Mutation in Papillon and Phalène Dogs with Progressive Retinal Atrophy. PLoS ONE 8:e72122, 2013.

128. Progressive Retinal Atrophy, (PRA); mutation originally found in Basenji

Disease Category Type
ocular

Description
Progressive retinal atrophy (PRA) comprises a group of genetically-inherited diseases affecting dogs of various breeds. PRA is characterized by retinal degeneration and progressive loss of vision culminating in blindness. PRA is known to affect over 100 breeds. Causative gene mutations have been identified in several breeds, but some remain unidentified. PRA affecting the Basenji breed is caused by a mutation in the SAG gene. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
In Basenjis, the onset of clinical signs is observed with initial vision loss in dim light (night blindness) that gradually progresses to total blindness. The first signs are caused by degeneration of rod photoreceptor cells required for vision in dim light followed by reduction of the visual field and blindness as the cone cells of the retina also degenerate. The adult onset of signs occurs typically at 5-6 years of age. Affected dogs usually retain adequate daylight vision for many years, sometimes throughout their natural lifespan. Affected dogs usually adjust well to their normal surroundings despite the reduction of visual field and night blindness.

Mutation Found In:
Basenji

Gene Variant Tested
SAG

Clinical Signs
progressive vision loss, night blindness, reduction of the visual field, and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Goldstein O, Jordan JA, Aguirre GD, Acland, GM. A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs. Mol Vis 19:1871-84, 2013.

129. Progressive Retinal Atrophy; mutation originally found in Swedish Vallhund

Disease Category Type
ocular

Description
Progressive retinal atrophy (PRA) is an ocular disorder encountered in several dog breeds. PRA is characterized by retinal degeneration and progressive loss of vision leading eventually to blindness. Many of the causative mutations behind different forms of PRA have been identified but some of them are still unidentified. A strong candidate causal mutation for PRA in the Swedish Vallhund breed has been identified, however it does not explain all cases of PRA in the breed. Dogs that are homozygous for this mutation have a 20-fold increased risk of retinopathy.

Clinical Overview
Typically, the first signs of PRA in Swedish Vallhund can be observed at 4 years of age. Degeneration of the light sensitive photoreceptor cells, called rod cells, start causing night blindness around 6 years of age. The progressive condition also results in the loss of cone cells. However, the condition rarely progresses to complete blindness and affected dog often maintain sufficient day vision for several years, often through their natural life span. It must be noted, that even when the most typical age of onset is around 4 years of age, the age of onset can vary from 1 year to up to 12 years.

Mutation Found In:
Swedish Vallhund

Gene Variant Tested
MERTK

Clinical Signs
progressive vision loss, night blindness, reduction of the visual field, and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Cooper AE, Ahonen SJ, Rowlan JS, Duncan A, Seppälä EH, Vanhapelto P, Lohi H, Komáromy AM. A Novel Form of Progressive Retinal Atrophy in Swedish Vallhund Dogs. PLoS ONE, 9(9): e106610, 2014. Pubmed: 25198798.

Ahonen SJ, Arumilli M, Seppälä EH, Hakosalo O, Kaukonen MK, Komáromy AM, Lohi H (2014). Increased Expression of MERTK is Associated with A Unique Form of Canine Retinopathy. PloS ONE, Dec 17;9(12): e114552, 2014. Pubmed: 25517981.

Everson R, Pettitt L, Forman OP, Dower-Tylee O, McLaughlin B, Ahonen S, Kaukonen M, Komáromy AM, Lohi H, Mellersh CS, Sansom J, Ricketts SL. An intronic LINE-1 insertion in MERTK is strongly associated with retinopathy in Swedish Vallhund dogs. PLoS One. 2017 Aug 16;12(8):e0183021. doi: 10.1371/journal.pone.0183021. eCollection 2017.

130. Protein Losing Nephropathy, (PLN); NPHS1 gene variant

Disease Category Type
renal

Description
Protein losing nephropathy (PLN) is a renal disorder in which affected dogs lose protein through their kidneys, resulting in protein excretion in their urine. Protein losing nephropathy has a complex background and several different genes and environmental factors can contribute to the onset of symptoms. The clinical signs include weight loss and fatigue. The condition is progressive, resulting in symptoms of kidney disease such as increased drinking (polydipsia), increased urination (polyuria), decrease appetite, nausea, and vomiting. Two risk alleles associated with PLN have been identified in Soft Coated Wheaton Terriers, NPHS1 and KIRREL2. These were also found in a single affected Airedale Terrier. Dogs homozygous for both risk alleles have an increased risk of developing protein losing nephropathy.

Clinical Overview
Protein losing nephropathy is characterized by high levels of protein in the urine. Clinical signs include weight loss, fatigue, vomiting, and diarrhea. Increased drinking and urination are also typically observed. Accumulation of fluid in the abdominal cavity (ascites) and chest cavity (pleural effusion), high blood pressure, and high cholesterol can be associated with the disorder as well. A characteristic sign of protein losing nephropathy is low albumin concentration in the blood (hypoalbuminemia) and presence of excess albumin in the urine (proteinuria). Protein losing nephropathy is an adult-onset disorder with onset of signs at the age of 4-8 years. Severity of signs can vary from mild to severe. Affected dogs can be treated with medication and controlled diet and those with mild signs can usually have a normal lifespan. Dogs suffering from severe signs have a shorter life expectancy.

Mutation Found In:
Airedale Terrier, Soft Coated Wheaten Terrier

Gene Variant Tested
NPHS1

Clinical Signs
proteinuria, hypoalbuminemia, hypercholesterolemia, polyuria, polydipsia, anorexia, vomiting, diarrhea

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Littman MP, Wiley CA, Raducha MG, Henthorn PS. Glomerulopathy and mutations in NPHS1 and KIRREL2 in soft-coated Wheaton Terrier dogs. Mamm Genome 24:119-26, 2013.

131. Pyruvate Dehydrogenase Phosphatase 1 (PDP1) Deficiency

Disease Category Type
metabolic

Description
Pyruvate dehydrogenase phosphatase 1 (PDP1) deficiency is an inherited metabolic disorder encountered in the Clumber Spaniel and the Sussex Spaniel. This disorder is due to a deficit of the PDP1 enzyme which is normally involved in the activation of the pyruvate dehydrogenase complex in cellular metabolism. PDP1 deficiency is characterized by exercise intolerance and lactic acidosis, but affected dogs can ease symptoms by resting. The disorder is inherited as an autosomal recessive trait.

Clinical Overview
PDP1 deficiency affects the energy metabolism of the muscles. Physical exercise causes lactic acid build up leading to low blood pH and lactic acidosis. Affected dogs suffer from exercise intolerance and they may collapse during physical activity. Affected dogs can ease the symptoms of PDP1 deficiency by resting. The exercise intolerance is usually detected in the first year of a dog's life.

Mutation Found In:
Clumber Spaniel, Sussex Spaniel

Gene Variant Tested
PDP1

Clinical Signs
exercise intolerance and lactic acidosis

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Cameron JM, Maj MC, Levandovskiy V, MacKay N, Shelton GD, Robinson BH. Identification of a canine model of pyruvate dehydrogenase phosphatase 1 deficiency. Mol Genet Metab 90:15-23, 2007.

132. Pyruvate Kinase Deficiency; mutation originally found in Pug

Disease Category Type
blood

Description
Pyruvate kinase deficiency is a disorder causing hemolytic anemia and usually results in the death of affected individuals before they reach 5 years of age. The disease follows an autosomal recessive mode of inheritance.

Clinical Overview
Pyruvate kinase (PK) is an enzyme needed for normal energy production by the red blood cells. PK deficiency affects the life span of erythrocytes (red blood cells) that break down particularly easily, which results in hemolytic anemia. Clinical signs include reduced exercise tolerance, weakness, pale mucous membranes, slowed growth, and a heart murmur. Accumulation of iron released from red blood cells damages the liver and bone marrow, resulting in liver failure and abnormal bone density. The disease leads to the death of the affected dog, usually at less than 5 years of age.

Mutation Found In:
Pug

Gene Variant Tested
PKLR Pug

Clinical Signs
anemia, drowsiness, pale mucous membranes, enlargement of the spleen and liver, osteosclerosis, and myelofibrosis

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Giger U, Noble NA. Determination of Erythrocyte Pyruvate Kinase Deficiency in Basenjis with Chronic Hemolytic Anemia. J Am Vet Med Assoc 198:1755-1761, 1991.

Gultekin GI, Raj K, Foureman P, Lehman S, Manhart K, Abdulmalik O, Giger U Erythrocytic pyruvate kinase mutations causing hemolytic anemia, osteosclerosis, and secondary hemochromatosis in dogs. J Am Vet Med Assoc 26:935-44, 2012.

Searcy GP, Miller DR, Tasker JB Congenital hemolytic anemia in the Basenji dog due to erythrocyte pyruvate kinase deficiency. Can J Comp Med 35:67-70, 1971.

Skelly BJ, Wallace M, Rajpurohit YR, Wang P, Giger U. Identification of a 6 base pair insertion in West Highland White Terriers with erythrocyte pyruvate kinase deficiency. Am J Vet Res 60:1169-1172, 1999.

Whitney KM, Lothrop CD. Genetic test for pyruvate kinase deficiency of basenjis. J Am Vet Med Assoc 207:918-921, 1995.

133. Pyruvate Kinase Deficiency; mutation originally found in West Highland White Terrier

Disease Category Type
blood

Description
Pyruvate kinase deficiency is a disorder causing hemolytic anemia and usually results in the death of affected individuals before they reach 5 years of age. The disease follows an autosomal recessive mode of inheritance.

Clinical Overview
Pyruvate kinase (PK) is an enzyme needed for normal energy production by the red blood cells. PK deficiency affects the life span of erythrocytes (red blood cells) that break down particularly easily, which results in hemolytic anemia. Clinical signs include reduced exercise tolerance, weakness, pale mucous membranes, slowed growth, and a heart murmur. Accumulation of iron released from red blood cells damages the liver and bone marrow, resulting in liver failure and abnormal bone density. The disease leads to the death of the affected dog, usually at less than 5 years of age.

Mutation Found In:
Cairn Terrier, West Highland White Terrier

Gene Variant Tested
PKLR West Highland White Terrier

Clinical Signs
anemia, drowsiness, pale mucous membranes, enlargement of the spleen and liver, osteosclerosis, and myelofibrosis

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Giger U, Noble NA. Determination of Erythrocyte Pyruvate Kinase Deficiency in Basenjis with Chronic Hemolytic Anemia. J Am Vet Med Assoc 198:1755-1761, 1991.

Gultekin GI, Raj K, Foureman P, Lehman S, Manhart K, Abdulmalik O, Giger U Erythrocytic pyruvate kinase mutations causing hemolytic anemia, osteosclerosis, and secondary hemochromatosis in dogs. J Am Vet Med Assoc 26:935-44, 2012.

Searcy GP, Miller DR, Tasker JB Congenital hemolytic anemia in the Basenji dog due to erythrocyte pyruvate kinase deficiency. Can J Comp Med 35:67-70, 1971.

Skelly BJ, Wallace M, Rajpurohit YR, Wang P, Giger U. Identification of a 6 base pair insertion in West Highland White Terriers with erythrocyte pyruvate kinase deficiency. Am J Vet Res 60:1169-1172, 1999.

Whitney KM, Lothrop CD. Genetic test for pyruvate kinase deficiency of basenjis. J Am Vet Med Assoc 207:918-921, 1995.

134. QT Syndrome

Disease Category Type
cardiac

Description
QT Syndrome is a rare cardiac disease associated with sudden death. The disease predisposes to fatal ventricular arrhythmias. Affected dogs exhibit no other cardiac symptoms before death. Some affected dogs may have a detectable systolic murmur or increased heart rate upon auscultation. The most characteristic sign of the disease is a prolonged QT-interval on ECG. The disease has been reported in the English Springer Spaniel. The mode of inheritance is most probably autosomal dominant.

Clinical Overview
Affected dogs are presented with an abnormally long QT-interval in the ECG. Affected dogs have no other clinical signs but have a very high tendency for sudden death during activity. Sudden death is most probably due to acute ventricular fibrillation. Some affected dogs may have a systolic murmur or increased heart rate on physical examination and some may show an abnormal biphasic T-wave on ECG. There is no curative treatment for the disease. Beta blockers and avoidance of strenuous activity and excitement are commonly used for treatment but do not diminish the risk of sudden cardiac death.

Mutation Found In:
English Springer Spaniel

Gene Variant Tested
KCNQ1

Clinical Signs
prolonged QT interval, biphasic T-wave, sudden death

Mode of Inheritance
autosomal dominant

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Ware W, Reina-Doreste Y, Stern J, Meurs K. Sudden Death Associated with QT Interval Prolongation and KCNQ1 Gene Mutation in a Family of English Springer Spaniels. J Vet Intern Med;29:561-568, 2015.

135. Renal Cystadenocarcinoma and Nodular Dermatofibrosis, (RCND)

Disease Category Type
renal and dermal

Description
Renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a canine kidney cancer syndrome characterized by multifocal tumors in the kidneys, collagen nodules in the skin, and uterine leiomyomas in females. RCND is inherited in an autosomal dominant manner.

Clinical Overview
Renal cystadenocarcinoma and nodular dermatofibrosis is characterized by bilateral, multifocal tumors in the kidneys. Kidney cysts start to develop in puppyhood, but observable signs of kidney disease are usually present in dogs 7-8 years of age when tumors are larger in size and number. Typical signs of the kidney disorder are polydipsia, polyuria, loss of appetite, weight loss, ascites (accumulation of fluid in the peritoneal cavity), and vomiting. Most females develop uterine leiomyomas (benign smooth muscle tumors). Numerous firm nodules in the skin, consisting of dense collagen fibers are also present in RCND. Skin nodules are usually observable at the age of five years and they can be seen especially in the area of head and limbs. Skin nodules grow slowly over a long period of time and can cause skin lesions at an older age. Skin nodules are usually not associated with discomfort but skin lesions can be painful. Many affected dogs can live many years with subclinical disease. In some cases, the clinical signs are mild and appear at an older age.

Mutation Found In:
German Shepherd Dog

Gene Variant Tested
FLCN

Clinical Signs
bilateral, multifocal tumors in the kidneys, uterine leiomyomas, collagen nodules in the skin, and skin lesions

Mode of Inheritance
autosomal dominant

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Lingaas F, Comstock KE, Kirkness, EF, Srensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.Hum Mol Genet 12:3043-53, 2003.

136. Rod-Cone Dysplasia 1, (rcd1); mutation originally found in Irish Setter

Disease Category Type
ocular

Description
Rod-cone dysplasia 1 (rcd1) in Irish Setters and Irish Red and White Setters is an inherited eye disorder that causes photoreceptor degeneration that results in blindness. It is inherited in an autosomal recessive manner.

Clinical Overview
The first clinical signs include night blindness from rod cell degeneration and begin in Irish Setters usually at the age of 6-8 weeks. The disorder will progress as the cone cells also degrade impairing day vision, and eventually the disorder will result in complete blindness. rcd1 in Irish Setters is more aggressive than the other variant, causing blindness in the first year of age.

Mutation Found In:
Irish Setter, Irish Red and White Setter

Gene Variant Tested
PDE6B Irish Setter

Clinical Signs
night blindness, loss of vision, and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Dekomien G, Runte M, Gödde R, Epplen JT. Generalized progressive retinal atrophy of Sloughi dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene. Cytogenet Cell Genet 90:261-267, 2000.

Suber ML, Pittler SJ, Qin N, Wright GC, Holcombe V, Lee RH, Craft CM, Lolley RN, Baehr W, Hurwitz RL. Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc Natl Acad Sci U S A 1;90:3968-3972, 1993.

137. Rod-Cone Dysplasia 1a, (rcd1a); mutation originally found in Sloughi

Disease Category Type
ocular

Description
Rod-cone dysplasia 1a (rcd1a) in Sloughis is an inherited eye disorder that causes photoreceptor degeneration that results in blindness. It is inherited in an autosomal recessive manner.

Clinical Overview
The first clinical signs include night blindness from rod cell degeneration and begin in Sloughis at 2-3 years of age. The disorder will progress as the cone cells also degrade impairing day vision, and eventually the disorder will result in complete blindness. Disease progression or rcda in Sloughis may progress slowly.

Mutation Found In:
Sloughi

Gene Variant Tested
PDE6B Sloughi

Clinical Signs
night blindness, loss of vision, and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Dekomien G, Runte M, Gödde R, Epplen JT. Generalized progressive retinal atrophy of Sloughi dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene. Cytogenet Cell Genet 90:261-267, 2000.

Suber ML, Pittler SJ, Qin N, Wright GC, Holcombe V, Lee RH, Craft CM, Lolley RN, Baehr W, Hurwitz RL. Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc Natl Acad Sci U S A 1;90:3968-3972, 1993.

138. Rod-Cone Dysplasia 3, (rcd3)

Disease Category Type
ocular

Description
Rod-cone dysplasia 3 (rcd3) is an inherited eye disorder in the Cardigan Welsh Corgi, where development of retinal photoreceptors is disturbed. Rcd3 causes blindness and is inherited in an autosomal recessive manner.

Clinical Overview
As a first sign, an affected puppy has weak or non-existing night vision that is due to a developmental defect in retinal rod cells. The cone cells will show reduced function early on in an affected dog's lifetime and impair day vision. First ophthalmoscopic evidence is usually observed by the age of 3 months, followed by blindness usually by 1 year of age. Some dogs retain partial vision until 3-4 years of age.

Mutation Found In:
Cardigan Welsh Corgi, Pembroke Welsh Corgi

Gene Variant Tested
PDE6A Corgi

Clinical Signs
night blindness, loss of vision, and blindness

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Petersen-Jones SM, Entz DD, Sargan DR cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest Ophthalmol Vis Sci. 40(8):1637-1644, 1999.

Tuntivanich N, Pittler SJ, Fischer AJ, Omar G, Kiupel M, Weber A, Yao S, Steibel JP, Khan NW, Petersen-Jones SM Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation. Invest Ophthalmol Vis Sci. 50(2):801-813, 2009.

139. Sensory Ataxic Neuropathy, (SAN)

Disease Category Type
neurologic

Description
Sensory Ataxic Neuropathy (SAN) is a slowly progressive neurologic disorder causing uncoordinated movements and impaired balance. This variant is a risk factor causing an increased risk of disease for dogs with maternal Golden Retriever ancestry. The clinical significance of this variant in dogs lacking maternal Golden Retriever ancestry is not yet clear.

Clinical Overview
Dogs with SAN begin to exhibit evidence of the condition between 2 to 8 months of age. However, many dogs with the genetic disease variant will never go on to develop clinical signs of the disease. In dogs with the disease variant that do develop clinical disease, the clinical signs appear insidiously, with affected dogs exhibiting ataxia and dysmetria. Decreased spinal reflexes and abnormal postural reactions are also seen, though they are not accompanied by muscle atrophy. Disease progression is slow but euthanasia is often elected while the dog is still a juvenile. SAN has only been found to cause disease in Golden Retrievers and when inherited through the maternal lines, and it should be noted that the variant is a risk factor meaning that not all Golden Retrievers with copies of the variant will go on to exhibit clinical signs. Akitas have been found to have an alternative genetic variant in the exact same location as the mutation identified in Golden Retrievers. While the two mutations cannot be distinguished by the technology used in this test, the Akita variant is neutral and does not cause the condition, so dogs inheriting this neutral variant are not affected. Therefore, the clinical significance of this disease variant in dogs where it has not been inherited through maternal lines of Golden Retriever ancestry is not yet clear.

Mutation Found In:
Golden Retriever

Gene Variant Tested
tRNATyr

Clinical Signs
ataxia, dysmetria, and difficulty maintaining balance

Mode of Inheritance
mitochondrial

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Jäderlund KH, Orvind E, Johnsson E, Matiasek K, Hahn CN, Malm S, Hedhammar A. A neurologic syndrome in Golden Retrievers presenting as a sensory ataxic neuropathy. J Vet Intern Med. 2007 Nov-Dec; 21(6):1307-15.

Baranowska I, Jäderlund KH, Nennesmo I, Holmqvist E, Heidrich N, Larsson NG, Andersson G, Wagner EG, Hedhammar A, Wibom R, Andersson L. Sensory ataxic neuropathy in golden retriever dogs is caused by a deletion in the mitochondrial tRNATyr gene. PLoS Genet. 2009 May; 5(5):e1000499.

140. Sensory Neuropathy; mutation originally found in Border Collie

Disease Category Type
neurologic

Description
Sensory neuropathy is a rare, severe neurological disorder caused by the degeneration of nerve cells. Clinical signs emerge in puppyhood. Affected dogs have proprioceptive deficits and harm themselves due to lack of pain sensation. The disorder is inherited in an autosomal recessive manner.

Clinical Overview
Clinical signs are detectable in puppies from two to seven months of age. Clinical signs include incoordination of gait (ataxia), knuckling of the paws, hyperextension of the limbs, and self-mutilation of the limbs. The hind legs are usually most severely affected. Loss of sensation is progressive and affects all limbs. Urinary incontinence and regurgitation can occur in the later stages of the disorder.

The disorder is caused by the degeneration and loss of nerve fibers in sensory, and to a smaller extent motor, nerve fibers. The prognosis is grave.

Mutation Found In:
Border Collie

Gene Variant Tested
FAM134B

Clinical Signs
uncoordinated gait, knuckling of hindpaws, self-mutilation

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Forman OP, Hitti R, Pettitt L, Jenkins C, O'Brien D, Shelton G, De Risio L, Quintana R, Beltran E, Mellersh C. An Inversion Disrupting FAM134B Is Associated with Sensory Neuropathy in the Border Collie Dog Breed. G3 (Bethesda). 2016 Sep 8;6(9):2687-92. doi: 10.1534/g3.116.027896.

141. Severe Combined Immunodeficiency, (SCID); mutation originally found in Frisian Water Dogs

Disease Category Type
immunologic

Description
Severe combined immunodeficiency (SCID) is an inherited immunological disorder characterized by the dysfunction of T- and B-lymphocytes. Immunodeficiency predisposes affected dogs to recurrent infections. Clinical signs include failure to thrive, diarrhea, seizures, and neurological signs. The underlying genetic mutation has been identified in Frisian Water Dogs or Wetterhouns. SCID is inherited in an autosomal recessive manner.

Clinical Overview
Severe combined immunodeficiency is characterized by T- and B-lymphocyte dysfunction resulting in a non-functional immune system. Affected dogs are predisposed to infections. The onset of signs typically occurs at 7-8 weeks of age and includes lethargy, poor growth, vomiting, diarrhea, ataxia, seizures, and blindness. Affected dogs rarely survive over 4 months of age. There is no treatment available for SCID.

Mutation Found In:
Frisian Water Dog

Gene Variant Tested
RAG1

Clinical Signs
poor growth, diarrhea, vomiting, seizures, ataxia, blindness, depletion of lymphoid tissues, reduced level of immunoglobulin, and reduced levels of lymphocytes

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Verfuurden B, Wempe F, Reinink P, van Kooten PJ, Martens E, Gerritsen R, Vos JH., Rutten VP, Leegwater PA. Severe combined immunodeficiency in Frisian Water Dogs caused by a RAG1 mutation. Genes Immun 12:310-3, 2011.

142. Skeletal Dysplasia 2, (SD2)

Disease Category Type
skeletal

Description
Skeletal dysplasia 2 (SD2) is an abnormality of skeletal development that causes mild disproportionate dwarfism or short-leggedness in Labrador Retrievers. The mutation has so far been described in working lines of this breed. The mode of inheritance is autosomal recessive.

Clinical Overview
Affected dogs have shorter limbs, but otherwise normal build. Forelegs are usually slightly more affected than hind legs. Shoulder height is lower (<50 cm) compared to the international breed standard (54-57 cm), which can be observed after the dog’s growth period is finished. In contrast to other skeletal dyplasias, no auditory problems, deafness, or secondary joint problems are associated with SD2. Because the mutation is superimposed on the normal variation seen in the breed, it can be difficult to identify the trait in some individuals.

Mutation Found In:
Labrador Retriever

Gene Variant Tested
COL11A2

Clinical Signs
mild disproportionate dwarfism

Mode of Inheritance
autosomal recessive

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Frischknecht M, Niehof-Oellers H, Jagannathan V, Owczarek-Lipska M, Drögemüller C, Dietschi E, Dolf G, Tellhelm B, Lang J, Tiira K, Lohi H, Leeb T. A COL11A2 mutation in Labrador retrievers with mild disproportionate dwarfism. PLoS One. 2013;8(3):e60149.

143. Spinocerebellar Ataxia or Late-Onset Ataxia, (SCA, LOA)

Disease Category Type
neurologic

Description
Spinocerebellar ataxia is a neurological disorder characterized by uncoordinated movements and impaired balance. In comparison to other early-onset ataxias, however, it has a later onset and slower progression. Clinical signs are usually first detected before the dog is a year old. A mutation in the CAPN1 gene is believed to be associated with spinocerebellar ataxia in the Parson Russell Terrier; this mutation is inherited in an autosomal recessive manner.

Clinical Overview
The onset of clinical signs is usually at the age of 6-12 months. The first observable sign of spinocerebellar ataxia is lack of muscle coordination, particularly evident in the pelvic limbs. Affected dogs have difficulty climbing stairs and jumping. The clinical signs also include hypermetria (overreaching movements) and loss of balance. The condition is progressive during the initial weeks or months of the disease followed by a certain degree of stabilization. However, intermittent worsening may also occur. The affected dogs are often euthanized due to difficulties walking. Generalized seizures, exercise intolerance, and behavioral changes have also been described in some cases.

Mutation Found In:
Jack Russell Terrier, Parson Russell Terrier

Gene Variant Tested
CAPN1

Clinical Signs
ataxia, difficulty in climbing stairs and jumping, hypermetria, and impaired balance

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Forman OP, De Risio L, Mellersh CS. Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed. PLoS One 8:e64627, 2013.

Wessmann A, Goedde T, Fischer A, Wohlsein P, Hamann H, Distl O, Tipold A. Hereditary ataxia in the Jack Russell Terrier - clinical and genetic investigations. J Vet Intern Med 2004;18:515-521.

144. Spinocerebellar Ataxia with Myokymia and/or Seizures, (SAMS)

Disease Category Type
neurologic

Description
Spinocerebellar ataxia is a neurological disorder characterized by uncoordinated movements and impaired balance. Patients exhibiting this variant of the condition may also exhibit myokymia (twitching of muscles) and/or seizures. Clinical signs are usually first detected before the dog is 6 months old. A mutation in the KCNJ10 gene is believed to be associated with SAMS in several terriers; this mutation is inherited in an autosomal recessive manner.

Clinical Overview
The onset of clinical signs is usually at the age of 2-6 months. The first observable sign of spinocerebellar ataxia is lack of muscle coordination, particularly evident in the pelvic limbs. They may also exhibit hypermetria, myokymia (muscle fasciculations), neuromyotonia (muscle twitching at rest), excessive facial rubbing, and seizures. Affected dogs are often euthanized due to difficulties walking.

Mutation Found In:
Jack Russell Terrier, Parson Russell Terrier, Smooth Fox Terrier, Toy Fox Terrier

Gene Variant Tested
KCNJ10

Clinical Signs
ataxia, difficulty in climbing stairs and jumping, hypermetria, and impaired balance

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Gilliam D, O'Brien DP, Coates JR, Johnson GS, Johnson GC, Mhlanga-Mutangadura T, Hansen L, Taylor JF, Schnabel RD. A homozygous KCNJ10 mutation in Jack Russell Terriers and related breeds with spinocerebellar ataxia with myokymia, seizures, or both. J Vet Intern Med. 2014 May-Jun;28(3):871-7.

Rohdin C, Gilliam D, O'Leary CA, O'Brien DP, Coates JR, Johnson GS, Jäderlund KH. A KCNJ10 mutation previously identified in the Russell group of terriers also occurs in Smooth-Haired Fox Terriers with hereditary ataxia and in related breeds. Acta Vet Scand. 2015 May 23;57:26.

145. Spondylocostal Dysostosis

Disease Category Type
skeletal

Description
Spondylocostal dysostosis is a severe developmental disorder of the Miniature Schnauzer. The disease leads to stillbirth or death soon after birth. The disorder is characterized by shortened body length and reduced hindquarters. Affected dogs may be presented with other developmental anomalies in association with skeletal abnormalities. The mode of inheritance is autosomal recessive.

Clinical Overview
Spondylocostal dysostosis causes severe malformations of the axial skeleton. Affected puppies are stillborn or die soon after birth. This is presumably caused by impaired respiratory function resulting from truncal shortening and rib fusion. Affected puppies have a comma-like appearance due to reduction of the hindquarters, malformations and fusions of the ribs, and reduced body length. Some affected puppies have other developmental anomalies upon exam.

Mutation Found In:
Miniature Schnauzer

Gene Variant Tested
HES7

Clinical Signs
stillbirth or death soon after birth, short trunk, skeletal malformations, rib anomalies

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Willet C, Makara M, Reppas G, Tsoukalas G, Malik R, Haase B, Wade C. Canine Disorder Mirrors Human Disease: Exonic Deletion in HES7 Causes Autosomal Recessive Spondylocostal Dysostosis in Miniature Schnauzer Dogs. PLoS ONE 10(2): e0117055, 2015.

146. Spongy Degeneration with Cerebellar Ataxia, (SDCA1); mutation originally found in Belgian Shepherd Dog and Malinois

Disease Category Type
neurologic

Description
In humans, SeSAME/EAST is a rare hereditary neurological disorder. Belgian Shepherds, especially the Malinois type, can suffer from a syndrome that is similar to this human condition. This syndrome in Belgian Shepherds is called spongy degeneration with cerebellar ataxia. The inheritance pattern is autosomal recessive.

Clinical Overview
The age of onset of SDCA is usually 6-8 weeks. The first observable sign is poor coordination of movements (ataxia). Affected dogs may also suffer from episodic myokymia and/or seizures. Myokymia is characterized by uncontrollable twitching of the muscles that tends to run through a muscle in waves. Myokymia episodes can be precipitated by exercise or excitement. The condition can lead to neuromyotonia (generalized muscle stiffness). Neuromyotonia episodes are incapacitating attacks during which the dog becomes rigid and falls down. Affected dogs remain aware of their surroundings during neuromytonia attacks and are at risk of overheating. Long-term prognosis of this disorder is poor.

Mutation Found In:
Belgian Shepherd Dog, Malinois

Gene Variant Tested
KCNJ10

Clinical Signs
ataxia, myokymia, neuromyotonia, seizures

Mode of Inheritance
autosomal recessive

Disease Severity
considerable discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Mauri N, Kleiter M, Leschnik M, Högler S, Dietschi E, Wiedmer M, Dietrich J, Henke D, Steffen F, Schuller S, Gurtner C, Stokar-Regenscheit N, O’Toole D, Bilzer T, Herden C, Oevermann A, Jagannathan V, Leeb T. A Missense Variant in KCNJ10 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1). G3 (Bethesda). 2017 Feb; 7(2): 663–669. Published online 2016 Dec 21. doi: 10.1534/g3.116.038455 PMCID: PMC5295610

Van Poucke M, Stee K, Bhatti S, Vanhaesebrouck A, Bosseler L, Peelman L, Van Ham L. The novel homozygous KCNJ10 c.986T4C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs. Eur J Hum Genet. 2017 Feb;25(2):222-226. doi: 10.1038/ejhg.2016.157. Epub 2016 Dec.

147. Trapped Neutrophil Syndrome, (TNS)

Disease Category Type
blood

Description
Trapped neutrophil syndrome (TNS) is a white blood cell disorder in Border Collies. TNS follows an autosomal recessive mode of inheritance. TNS is a severe disease and affected dogs have a shorter life expectancy.

Clinical Overview
Neutrophils are white blood cells that play a key role in activating the immune system. In TNS, blood cells fail to be released from the bone marrow, which results in low neutrophil numbers circulating in the blood. As a consequence, the dog is exceptionally susceptible to infections and suffers from chronic inflammatory conditions such as arthritis. Clinical signs are usually observed at the age of 6 to 12 weeks. Affected puppies are often smaller than their littermates and described to have ferret-like facial features due to an abnormal craniofacial development with narrowed, elongated skull shape. For some affected dogs, clinical signs can be mild and go unnoticed until adulthood. Nevertheless, TNS is a severe disease and affected dogs have a shorter life expectancy.

Mutation Found In:
Border Collie, Mixed breed

Gene Variant Tested
VPS13B

Clinical Signs
neutropenia, myeloid hyperplasia, chronic infections, abnormal craniofacial features, and delayed development

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Shearman JR, Wilton AN. A canine model of Cohen syndrome: Trapped Neutrophil Syndrome. BMC Genomics 23:258, 2011.

148. von Willebrand's Disease (vWD) Type 1; mutation originally found in Doberman Pinscher

Disease Category Type
blood

Description
The clotting pathway is a complex process. The vWF glycoprotein complexes with factor VIII and both are required for platelet adhesion and preventing the rapid clearance of factor VIII. Von Willebrand’s disease (vWD) is a bleeding disorder affecting multiple breeds and several genetic variants have been characterized. Type 1 is the mildest form of vWD in which the level of von Willebrand’s factor is reduced though all the multimers are present. Many cases are subclinical but can be associated with an increased bleeding tendency after surgery or trauma. The disease is inherited in an autosomal recessive manner, though some carriers can have clinical signs.

Clinical Overview
Type 1 von Willebrand’s disease is the mildest form of vWD and while many dogs may be subclinical, some dogs may exhibit more severe clinical signs. Excessive bleeding may be observed after a trauma or surgery. Not all affected pups will exhibit the same severity of clinical signs as these are related to the amount of vWF present, which vary between affected individuals. An affected dog will have a normal PT/aPTT but have prolonged bleeding (which can be assessed using a buccal-mucosal bleeding time). When assayed, these dogs usually have low levels of vWF. Some carriers may show clinical signs though dogs with two copies of the mutation tend to be more severely affected. Medications known to interfere with clotting should be avoided. Some dogs may exhibit some improvement when treated with desmopressin acetate.

Mutation Found In:
Bernese Mountain Dog, Coton De Tulear, Doberman Pinscher, Drentse Patrijshond, German Pinscher, Kerry Blue Terrier, Manchester Terrier, Papillon, Pembroke Welsh Corgi, Poodle, Stabyhoun

Gene Variant Tested
VWF Type1

Clinical Signs
bleeding tendency

Mode of Inheritance
autosomal recessive, though some carriers may exhibit clinical signs

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Brooks MB, Erb HN, Foureman PA, Ray K. von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers. Am J Vet Res. 62(3):364-369, 2001.

Ackerman L. The Genetic Connection. Lakewood: American Animal Hospital Association Press, 2011.

149. von Willebrand's Disease (vWD) Type 2; mutation originally found in German Wirehaired Pointer

Disease Category Type
blood

Description
The clotting pathway is a complex process. The vWF glycoprotein complexes with factor VIII and both are required for platelet adhesion and preventing the rapid clearance of factor VIII. Von Willebrand’s disease (vWD) is a bleeding disorder affecting multiple breeds and several genetic variants have been characterized. Type 2 vWD affects several breeds, but the mutation tested here has been found to only be predictive of the risk of developing the condition in German Shorthaired Pointers and German Wirehaired Pointers. The disease causes moderate to severe bleeding tendency due to low level and abnormal structure of von Willebrand’s factor. The mode of inheritance is autosomal recessive.

Clinical Overview
Type 2 von Willebrand’s disease is a moderate to severe clotting disorder. Typical symptoms include mucosal bleeding, such as epistaxis, bleeding from the gums, gastrointestinal bleeding, and blood in the urine. Exceptionally excessive and prolonged bleeding may be observed after a trauma or surgery, and spontaneous bleeding may also be encountered. This condition can lead to death if untreated.

Mutation Found In:
German Shorthaired Pointer, German Wirehaired Pointer

Gene Variant Tested
VWF Type2

Clinical Signs
severe bleeding tendency

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Kramer JW, Venta PJ, Klein SR, Cao Y, Schall WD, Yuzbasiyan-Gurkan V A von Willebrand's factor genomic nucleotide variant and polymerase chain reaction diagnostic test associated with inheritable type-2 von Willebrand's disease in a line of german shorthaired pointer dogs. Vet Pathol 41(3):221-228, 2004.

Vos-Loohuis M. van Oost BA, Dangel C, Langehein-Detsch I, Leegwater PA. A novel VWF variant associated with type 2 von Willebrand disease in German Wirehaired Pointers and German Shorthaired Pointers. Anim Gent. Apr 2017.

Ackerman L. The Genetic Connection. Lakewood: American Animal Hospital Association Press, 2011.

150. von Willebrand's Disease (vWD) Type 3; mutation originally found in Kooiker Hound

Disease Category Type
blood

Description
The clotting pathway is a complex process. The vWF glycoprotein complexes with factor VIII and both are required for platelet adhesion and preventing the rapid clearance of factor VIII. Von Willebrand’s disease (vWD) is a bleeding disorder affecting multiple breeds and several genetic variants have been characterized. Type 3 is the most severe form of vWD. The disease is inherited in an autosomal recessive manner.

Clinical Overview
Type 3 von Willebrand’s disease is a moderate to severe clotting disorder. Typical clinical signs include mucosal bleeding, such as nose bleeding, bleeding from the gums, gastrointestinal bleeding, and blood in the urine. Exceptionally excessive and prolonged bleeding may be observed after a trauma or surgery, and spontaneous bleeding may also be encountered. This condition can lead to death if untreated. Most affected dogs will have a normal PT/aPTT but have prolonged bleeding (which can be assessed using a buccal-mucosal bleeding time). When assayed, these dogs have no appreciable levels of vWF present.

Mutation Found In:
Kooiker Hound, Scottish Terrier, Shetland Sheepdog

Gene Variant Tested
VWF Type3

Clinical Signs
severe bleeding diathesis and death

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Pathak EJ. Type 3 von Willebrand's disease in a Shetland sheepdog. Can Vet J 45(8):685-687, 2004.

Rieger M, Schwarz HP, Turecek PL, Dorner F, van Mourik JA, Mannhalter C. Identification of mutations in the canine von Willebrand factor gene associated with type III von Willebrand disease. Thromb Haemost 80(2):332-337, 1998.

Venta PJ, Li J, Yuzbasiyan-Gurkan V, Brewer GJ, Schall WD. Mutation causing von Willebrand's disease in Scottish Terriers. J Vet Intern Med 14(1):10-9, 2000.

Ackerman L. The Genetic Connection. Lakewood: American Animal Hospital Association Press, 2011.

151. von Willebrand's Disease (vWD) Type 3; mutation originally found in Scottish Terrier

Disease Category Type
blood

Description
The clotting pathway is a complex process. The vWF glycoprotein complexes with factor VIII and both are required for platelet adhesion and preventing the rapid clearance of factor VIII. Von Willebrand’s disease (vWD) is a bleeding disorder affecting multiple breeds and several genetic variants have been characterized. Type 3 is the most severe form of vWD. The disease is inherited in an autosomal recessive manner.

Clinical Overview
Type 3 von Willebrand’s disease is a moderate to severe clotting disorder. Typical clinical signs include mucosal bleeding, such as nose bleeding, bleeding from the gums, gastrointestinal bleeding, and blood in the urine. Exceptionally excessive and prolonged bleeding may be observed after a trauma or surgery, and spontaneous bleeding may also be encountered. This condition can lead to death if untreated. Most affected dogs will have a normal PT/aPTT but have prolonged bleeding (which can be assessed using a buccal-mucosal bleeding time). When assayed, these dogs have no appreciable levels of vWF present.

Mutation Found In:
Kooiker Hound, Scottish Terrier, Shetland Sheepdog

Gene Variant Tested
VWF Type3 Scottish Terrier

Clinical Signs
severe bleeding diathesis and death

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Pathak EJ. Type 3 von Willebrand's disease in a Shetland sheepdog. Can Vet J 45(8):685-687, 2004.

Rieger M, Schwarz HP, Turecek PL, Dorner F, van Mourik JA, Mannhalter C. Identification of mutations in the canine von Willebrand factor gene associated with type III von Willebrand disease. Thromb Haemost 80(2):332-337, 1998.

Venta PJ, Li J, Yuzbasiyan-Gurkan V, Brewer GJ, Schall WD. Mutation causing von Willebrand's disease in Scottish Terriers. J Vet Intern Med 14(1):10-9, 2000.

Ackerman L. The Genetic Connection. Lakewood: American Animal Hospital Association Press, 2011.

152. von Willebrand's Disease (vWD) Type 3; mutation originally found in Shetland Sheepdog

Disease Category Type
blood

Description
The clotting pathway is a complex process. The vWF glycoprotein complexes with factor VIII and both are required for platelet adhesion and preventing the rapid clearance of factor VIII. Von Willebrand’s disease (vWD) is a bleeding disorder affecting multiple breeds and several genetic variants have been characterized. Type 3 is the most severe form of vWD. The disease is inherited in an autosomal recessive manner.

Clinical Overview
Type 3 von Willebrand’s disease is a moderate to severe clotting disorder. Typical clinical signs include mucosal bleeding, such as nose bleeding, bleeding from the gums, gastrointestinal bleeding, and blood in the urine. Exceptionally excessive and prolonged bleeding may be observed after a trauma or surgery, and spontaneous bleeding may also be encountered. This condition can lead to death if untreated. Most affected dogs will have a normal PT/aPTT but have prolonged bleeding (which can be assessed using a buccal-mucosal bleeding time). When assayed, these dogs have no appreciable levels of vWF present.

Mutation Found In:
Kooiker Hound, Scottish Terrier, Shetland Sheepdog

Gene Variant Tested
VWF Type3 Shetland Sheepdog

Clinical Signs
severe bleeding diathesis and death

Mode of Inheritance
autosomal recessive

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Pathak EJ. Type 3 von Willebrand's disease in a Shetland sheepdog. Can Vet J 45(8):685-687, 2004.

Rieger M, Schwarz HP, Turecek PL, Dorner F, van Mourik JA, Mannhalter C. Identification of mutations in the canine von Willebrand factor gene associated with type III von Willebrand disease. Thromb Haemost 80(2):332-337, 1998.

Venta PJ, Li J, Yuzbasiyan-Gurkan V, Brewer GJ, Schall WD. Mutation causing von Willebrand's disease in Scottish Terriers. J Vet Intern Med 14(1):10-9, 2000.

Ackerman L. The Genetic Connection. Lakewood: American Animal Hospital Association Press, 2011.

153. X-Linked Ectodermal Dysplasia, (XHED) or Anhidrotic Ectodermal Dysplasia

Disease Category Type
dermal

Description
X-linked ectodermal dysplasia (XHED) is a disorder causing skin, dental, and immune system problems in multiple breeds. The underlying genetic cause has been confirmed in German Shepherds; XHED follows X-linked inheritance. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
Signs of XHED include symmetrical hairlessness, missing or misshaped teeth, and lack of sweat glands. Affected dogs lack secondary hair and have no hair on their forehead or pelvis. The hair loss patterning can be seen soon after birth. Biopsies of affected areas reveal a complete absence of hair follicles and adnexa. Moreover, affected dogs suffer from dental abnormalities, such as missing or misshaped teeth. Other signs of XHED include decreased tear production, chronic nasal and ocular discharge, and a somewhat compromised immune system. XHED may also predispose affected dogs to generalized Demodex infections due to a weakened immune system.

Mutation Found In:
German Shepherd Dog

Gene Variant Tested
EDA

Clinical Signs
hair loss, dental abnormalities, and lack of sweat glands

Mode of Inheritance
X-linked

Disease Severity
mild discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Casal ML, Scheidt JL, Rhodes JL, Henthorn PS, Werner P. Mutation identification in a canine model of X-linked ectodermal dysplasia. Mamm Genome 16(7):524-531, 2005.

Lewis JR, Reiter AM, Mauldin EA, Casal ML. Dental abnormalities associated with X-linked hypohidrotic ectodermal dysplasia in dogs. Orthod Craniofac Res 13(1):40-47, 2010.

154. X-Linked Hereditary Nephropathy, (XLHN); mutation originally found in Navasota Dog

Disease Category Type
renal

Description
X-linked hereditary nephropathy is a kidney disorder observed in a group of mixed breed dogs named Navasota dogs. The disease causes proteinuria and results in juvenile-onset renal failure. It shows an X-linked mode of inheritance, as indicated in the name, and so the severe form of the disease is encountered only in males. In some cases, female carriers can develop a renal disease with milder symptoms.

Clinical Overview
XLHN affects the glomeruli in the renal corpuscle. The disease is caused by defective type IV collagen in the basal lamina. The main clinical sign of XLHN is proteinuria, which occurs around the age of 3 to 6 months. The disease leads to renal failure and eventually to death of affected males by the age of 9 to 15 months. Clinical signs of renal failure include excessive drinking, and frequent urination. Other possible signs are reduced growth, vomiting, diarrhea, and weight loss. Female carriers might exhibit proteinuria as a sign of mild renal disease, but the condition usually does not lead to renal failure before the age of five.

Mutation Found In:
Navasota

Gene Variant Tested
COL4A5 Navasota

Clinical Signs
excessive drinking and frequent urination, proteinuria, diarrhea, vomiting, weight loss, reduced growth, and renal failure

Mode of Inheritance
X-linked

Signs Seen in Affected Carriers
proteinuria if a female carriers

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Benali SL, Lees GE, Nabity MB, Aric A, Drigo M, Gallo E, Giantin M, Aresu L. X-Linked Hereditary Nephropathy in Navasota Dogs: Clinical Pathology, Morphology, and Gene Expression During Disease Progression. Vet Pathol. 2016 Jul;53(4):803-12.

Cox ML, Lees GE, Kashtan CE, Murphy KE. Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mamm Genome 14:396-403, 2003.

Zheng KQ, Thorner PS, Marrano P, Baumal R, Mcinnes RR. Canine X Chromosome-Linked Hereditary Nephritis - A Genetic Model for Human X-Linked Hereditary Nephritis Resulting from a Single Base Mutation in the Gene Encoding the alpha 5 Chain of Collagen Type IV. Proc Nat Acad Sci USA 91:3989-3993, 1994.

155. X-Linked Hereditary Nephropathy, (XLHN); mutation originally found in Samoyed

Disease Category Type
renal

Description
X-linked hereditary nephropathy is a kidney disorder observed in Samoyeds. The disease causes proteinuria and results in juvenile-onset renal failure. It shows an X-linked mode of inheritance, as indicated in the name, and so the severe form of the disease is encountered only in males. In some cases, female carriers can develop a renal disease with milder symptoms.

Clinical Overview
XLHN affects the glomeruli in the renal corpuscle. The disease is caused by defective type IV collagen in the basal lamina. The main clinical sign of XLHN is proteinuria, which occurs around the age of 3 to 6 months. The disease leads to renal failure and eventually to death of affected males by the age of 9 to 15 months. Clinical signs of renal failure include excessive drinking, and frequent urination. Other possible signs are reduced growth, vomiting, diarrhea, and weight loss. Female carriers might exhibit proteinuria as a sign of mild renal disease, but the condition usually does not lead to renal failure before the age of five.

Mutation Found In:
Samoyed

Gene Variant Tested
COL4A5 Samoyed

Clinical Signs
excessive drinking and frequent urination, proteinuria, diarrhea, vomiting, weight loss, reduced growth, and renal failure

Mode of Inheritance
X-linked

Signs Seen in Affected Carriers
proteinuria if a female carriers

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Bell RJ, Lees GE, Murphy KE. X chromosome inactivation patterns in normal and X-linked hereditary nephropathy carrier dogs. Cytogenet Genome Res 122:37-40, 2008.

Cox ML, Lees GE, Kashtan CE, Murphy KE. Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mamm Genome 14:396-403, 2003.

Zheng KQ, Thorner PS, Marrano P, Baumal R, Mcinnes RR. Canine X Chromosome-Linked Hereditary Nephritis - A Genetic Model for Human X-Linked Hereditary Nephritis Resulting from a Single Base Mutation in the Gene Encoding the alpha 5 Chain of Collagen Type IV. Proc Nat Acad Sci USA 91:3989-3993, 1994.

156. X-Linked Myotubular Myopathy; mutation originally found in Labrador Retriever

Disease Category Type
muscular

Description
The mutation causing X-linked myotubular myopathy was discovered in Labrador Retrievers. The disorder is characterized by early-onset pelvic limb weakness, progressing into an inability to move. Dogs with this disease generally present with muscle weakness, eating difficulties, respiratory distress, and delayed motor milestones. The disease follows an X-linked mode of inheritance. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
X-linked myotubular myopathy (XLMTM) is an inherited disorder that affects a myotubular protein involved in cellular transport particularly in the muscle cells. The clinical signs of X-linked myotubular myopathy can be seen in puppies as young as 10-19 weeks of age. Pelvic limb weakness is typically observed as one of the first signs. Affected dogs also lack patellar reflexes. X-linked myotubular myopathy is characterized by rapidly progressing muscle weakness and muscle atrophy. Affected dog won't be able to rise and move unassisted within a few weeks of the onset of clinical signs and may also have difficulties chewing and swallowing.

Mutation Found In:
Labrador Retriever

Gene Variant Tested
MTM1 Labrador Retriever

Clinical Signs
progressive muscle weakness, muscle atrophy, absence of patellar reflexes, and inability to rise and walk

Mode of Inheritance
X-linked

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Beggs AH, Böhm J, Snead E, Kozlowski M, Maurer M, Minor K, Childers MK, Taylor SM, Hitte C, Mickelson JR, Guo LT, Mizisin AP, Buj-Bello A, Tiret L, Laporte J, Shelton GD. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proc Natl Acad Sci U S A 107:14697-702, 2010.

157. X-Linked Progressive Retinal Atrophy 2, (XLPRA2)

Disease Category Type
ocular

Description
Progressive retinal atrophy (PRA) is an eye disorder encountered in several dog breeds. PRA is characterized by retinal degeneration and progressive loss of vision leading eventually to blindness. Many of the causative mutations behind different forms of PRA have been identified but some of them have not. X-linked progressive retinal atrophy 2 (XLPRA2) is an eye disorder causing early onset retinal degeneration in mixed breed dogs. Given males only have one X chromosome, the condition is seen most commonly in males as a single affected copy will cause the condition; females require two copies to exhibit the condition.

Clinical Overview
XLPRA2 is due to the degeneration of rod photoreceptors. Clinical signs such as night blindness and "tunnel vision" are usually observed already at the age of 6 to 7 weeks resulting in blindness by 2 years of age.

Mutation Found In:
Mixed breed

Gene Variant Tested
RPGR exonORF15

Clinical Signs
night blindness, tunnel vision, and blindness

Mode of Inheritance
X-linked

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Zhang Q, Acland GM, Wu WX, Johnson JL, Pearce-Kelling S, Tulloch B, Vervoort R, Wright FA, Aguirre GD. Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum Mol Gen 11(9):993-1003, 2002.

Zangerl B, Johnson JL, Acland GM, Aguirre GD. Independent Origin and Restricted Distribution of RPGR Deletions causing XLPRA. J Hered 98(5):526-530, 2007.

158. X-Linked Severe Combined Immunodeficiency, (XSCID); mutation originally found in Basset Hound

Disease Category Type
immunologic

Description
X-linked severe combined immunodeficiency (X-SCID) is a severe dysfunction of the immune system, reported in the Cardigan Welsh Corgi and the Basset Hound; this variant is associated with the latter. The mode of inheritance is X-linked recessive and, therefore, all affected dogs are males.

Clinical Overview
X-SCID is a severe immunodeficiency, which results from abnormally low levels of lymphocytes (white blood cells) and their dysfunctionality. Lymphatic tissue of affected dogs is also underdeveloped. Affected dogs are extremely susceptible to opportunistic infections and typically die at a very young age.

Mutation Found In:
Basset Hound

Gene Variant Tested
IL2RG Basset Hound

Clinical Signs
immunodeficiency, lymphopenia, lack of lymph nodes, vomiting, diarrhea, failure to thrive, and opportunistic infections

Mode of Inheritance
X-linked

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Henthorn PS, Somberg RL, Fimiani VM, Puck JM, Patterson DF, Felsburg PJ. IL-2R gamma gene microdeletion demonstrates that canine X- linked severe combined immunodeficiency is a homologue of the human disease. Genomics 23:69-74, 1994.

Somberg RL, Pullen RP, Casal ML, Patterson DF, Felsburg PJ, Henthorn PS. A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease. Vet Immunol Immunopathol 47:203-213, 1995.

159. X-Linked Severe Combined Immunodeficiency, (XSCID); mutation originally found in Cardigan Welsh Corgi

Disease Category Type
immunologic

Description
X-linked severe combined immunodeficiency (X-SCID) is a severe dysfunction of the immune system, reported in the Cardigan Welsh Corgi and the Basset Hound; this variant is associated with the former. The mode of inheritance is X-linked recessive and, therefore, all affected dogs are males.

Clinical Overview
X-SCID is a severe immunodeficiency, which results from abnormally low levels of lymphocytes (white blood cells) and their dysfunctionality. Lymphatic tissue of affected dogs is also underdeveloped. Affected dogs are extremely susceptible to opportunistic infections and typically die at a very young age.

Mutation Found In:
Cardigan Welsh Corgi

Gene Variant Tested
IL2RG Cardigan Welsh Corgi

Clinical Signs
immunodeficiency, lymphopenia, lack of lymph nodes, vomiting, diarrhea, failure to thrive, and opportunistic infections

Mode of Inheritance
X-linked

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Henthorn PS, Somberg RL, Fimiani VM, Puck JM, Patterson DF, Felsburg PJ. IL-2R gamma gene microdeletion demonstrates that canine X- linked severe combined immunodeficiency is a homologue of the human disease. Genomics 23:69-74, 1994.

Somberg RL, Pullen RP, Casal ML, Patterson DF, Felsburg PJ, Henthorn PS. A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease.Vet Immunol Immunopathol 47:203-213, 1995.

160. X-Linked Tremors; mutation originally found in English Springer Spaniel

Disease Category Type
neurologic

Description
X-linked tremors is a congenital neurological disorder of the central nervous system. Normally, oligodendrocytes produce an insulating myelin sheath that covers the axons of the nerves. Abnormal differentiation of oligodendrocytes causes lack of myelin production, tremors, and premature death. X-linked tremors is encountered in English Springer Spaniels. The condition is inherited in an X-linked recessive manner and only males are severely affected due to this X-linked inheritance. Females may exhibit mild tremors.

Clinical Overview
The first signs of X-linked tremors are usually observed by 2 weeks of age. Affected males suffer from severe tremors in the body, head, and limbs. The tremors tend to worsen with activity and decline during rest. Affected puppies suffering from tremors have difficulties standing, moving, and eating. The condition is progressive and leads to seizures. The affected dogs are smaller in size than their unaffected littermates. The life expectancy of affected dogs is not likely to be over 3-4 months. Females are carriers of the disorder and they may have mild tremors during puppyhood that resolve by the age of 4-6 weeks of age.

Mutation Found In:
English Springer Spaniel

Gene Variant Tested
PLP1

Clinical Signs
generalized tremor, reduced weight and body size, and convulsions

Mode of Inheritance
X-linked

Signs Seen in Affected Carriers
mild tremors during puppyhood that resolve if a female carrier

Disease Severity
severe discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
Nadon NL, Duncan ID, Hudson LD. A Point Mutation in the Proteolipid Protein Gene of the Shaking Pup Interrupts Oligodendrocyte Development. Development 110:529-537, 1990.

Griffiths IR, Duncan ID, McCulloch M, Harvey MJA. Shaking pups: A disorder of central myelination in the spaniel dog. J Neurol Sci 1981;50:423-433.

161. Xanthinuria, Type 1a; mutation originally found in Mixed breed

Disease Category Type
renal

Description
Xanthinuria is a hereditary disease that leads to excessive xanthine in the urine. Excessive xanthine can accumulate in the urinary tract causing formation of xanthine stones that can obstruct the urinary tract or kidneys. Different breeds suffer from different forms of xanthinuria. All known genetic defects causing xanthinuria are inherited in an autosomal recessive fashion.

Clinical Overview
This disorder can cause formation of urine stones throughout the upper and lower urinary tracts, including the urethra, bladder, ureters, and kidneys. Clinical signs of urolithiasis in the lower urinary tract include pain while urinating, bloody urine, and blockage of the urinary tract. Patients with urine stones are more susceptible to urinary tract infections. Blockage of the ureters and kidneys causes abdominal pain and kidney failure. A blocked urinary tract is a life-threatening condition that requires immediate veterinary care. The disorder can develop at any age, starting as early as when a pup is a few months of age. Males are more likely to form stones than females.

Mutation Found In:
Mixed breed

Gene Variant Tested
pending publication

Clinical Signs
difficulties when passing urine, pain when passing urine, inflammation in bladder, hematuria, kidney failure

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
E. Furrow, N. Tate, K. Minor, J. Mickelson, K. Peterson, and J. Lulich. Three diverse mutations underlying canine xanthine urolithiasis. ACVIM Research Report, 2016.

Tate N, Minor K, Mickelson J, Peterson K, Lulich JP, Furrow E. Three diverse mutations underlying canine xanthine urolithiasis. ISAG Oral Abstract, 2016.

162. Xanthinuria, Type 2a; mutation originally found in Toy Manchester Terrier

Disease Category Type
renal

Description
Xanthinuria is a hereditary disease that leads to excessive xanthine in the urine. Excessive xanthine can accumulate in the urinary tract causing formation of xanthine stones that can obstruct the urinary tract or kidneys. Different breeds suffer from different forms of xanthinuria. All known genetic defects causing xanthinuria are inherited in an autosomal recessive fashion.

Clinical Overview
This disorder can cause formation of urine stones throughout the upper and lower urinary tracts, including the urethra, bladder, ureters, and kidneys. Clinical signs of urolithiasis in the lower urinary tract include pain while urinating, bloody urine, and blockage of the urinary tract. Patients with urine stones are more susceptible to urinary tract infections. Blockage of the ureters and kidneys causes abdominal pain and kidney failure. A blocked urinary tract is a life-threatening condition that requires immediate veterinary care. The disorder can develop at any age, starting as early as when a pup is a few months of age. Males are more likely to form stones than females.

Mutation Found In:
Toy Manchester Terrier

Gene Variant Tested
pending publication

Clinical Signs
difficulties when passing urine, pain when passing urine, inflammation in bladder, hematuria, kidney failure

Mode of Inheritance
autosomal recessive

Disease Severity
moderate discomfort

References: Online Database
Online Mendelian Inheritance in Animals, OMIA (http://omia.angis.org.au/). Faculty of Veterinary Science, University of Sydney.

References: Scientific Articles
E. Furrow, N. Tate, K. Minor, J. Mickelson, K. Peterson, and J. Lulich. Three diverse mutations underlying canine xanthine urolithiasis. ACVIM Research Report, 2016.

Tate N, Minor K, Mickelson J, Peterson K, Lulich JP, Furrow E. Three diverse mutations underlying canine xanthine urolithiasis. ISAG Oral Abstract, 2016.

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