UC Davis School of Veterinary Medicine Veterinary Genetics Laboratory

German Shepherd Health Panel

Tests Offered:
CLAD | DM | HEMA | HUU | XHED | MPSVII | RCND

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Allow 5-10 business days for results.

Canine Leukocyte Adhesion Deficiency (CLAD or LAD)

Introduction

Canine leukocyte adhesion deficiency (CLAD) is an inherited blood disorder affecting Irish Setters and German Shepherd Dogs. The disease results from breed-specific mutations in genes that are integral to platelet and blood cell activity. Affected dogs have abnormal blood clotting and immune system functions. Affected German Shepherd Dogs and Irish Setters may present with lameness, recurrent skin infections including pyoderma (pus filled skin infections), furunculosis (boils) and ulceration, osteomyelitis (bone infections) and gingivitis. Additionally, Irish Setter pups may exhibit omphalophlebitis (umbilical vein infection), generalized lymphadenopathy (swollen or inflamed lymph nodes), and a failure to gain weight. Although some dogs can live for years with this condition, most affected dogs die early from severe infection or bleeding from an accidental injury, or during a surgical procedure. Veterinarians should be informed of affected dogs prior to any surgical procedures.

CLAD-Type I (reported as CLADis) in Irish Setters results from a single nucleotide change (c.107G>C) in the beta-2 integrin gene (ITGB2). CLAD-Type III (reported as CLADgs) in German Shepherd Dogs results from a 12bp insertion (c.1358_1359insAAGACGGCTGCC) in fermitin family member 3 gene (FERMT3).  In both cases, the disease is inherited in an autosomal recessive fashion, which means that males and females are equally affected and that two copies of the defective gene are needed to cause CLAD. Dogs with one normal and one affected gene (carriers) are normal and show no signs of disease.

The Veterinary Genetics Laboratory offers genetic tests for CLAD. Test results assist veterinarians with diagnosis of CLAD and help breeders identify carriers among breeding stock to avoid producing affected dogs. Matings between carriers are expected to produce 25% of affected puppies.

Testing recommended for: German Shepherd Dog, Irish Setter

Results reported as:

N/N Normal - no copies of the CLAD mutation
N/CLAD Carrier - 1 copy of the CLAD mutation
CLAD/CLAD Affected - 2 copies of the CLAD mutation

* Report will specify CLADis or CLADgs, according to breed

References:

Boudreaux MK, Wardrop KJ, Kiklevich V, Felsburg P, Snekvik K. (2010) A mutation in the canine Kindlin-3 gene associated with increased bleeding risk and susceptibility to infections. Thromb Haemost. 103(2):475-477.

Kijas JM, Bauer TR Jr, Gäfvert S, Marklund S, Trowald-Wigh G, Johannisson A, Hedhammar A, Binns M, Juneja RK, Hickstein DD, Andersson L. (1999) A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics 61, 101–110.

Degenerative Myelopathy

Introduction

Degenerative myelopathy (DM) is an inherited neurologic disorder of dogs similar to Lou Gehrig’s disease in humans and results from a mutation (c.118G>A) in the SOD1 gene. Affected dogs usually present clinical signs of disease in adulthood (at least 8 years of age) with gradual muscle wasting and loss of coordination that typically begins in the hind limbs because of nerve degeneration. Disease progression continues until the dog is unable to walk. Small breed dogs tend to progress more slowly. In late stages of the disease, dogs may become incontinent and the forelimbs may be affected. Affected dogs may fully lose the ability to walk 6 months to 2 years after the onset of signs. The disease is inherited in an autosomal recessive fashion with incomplete penetrance. Thus, two copies of the SOD1 mutation (DM/DM) confer increased risk for DM but not all DM/DM dogs across breeds will develop the disease. The variable presentation between breeds suggests that other genetic and environmental factors play a role in disease expression. There is ongoing research to identify other genetic factors that modify risk for DM in different breeds. In addition, similar disease presentation is observed in some animals lacking the SOD1 mutation. Breeding two carriers of the SOD1 mutation together is predicted to produce 25% pups that may develop DM.

The VGL offers a genetic test for the SOD1 c.118G>A mutation. Genetic screening helps breeders establish the genetic status of breeding stock and select mating pairs appropriately to reduce the risk of producing DM-affected offspring.

Testing is recommended for: many breeds

The Degenerative Myelopathy (DM) test is a patented test outside of the United States. The Veterinary Genetics Laboratory is not authorized to offer the DM test outside of the United States at this time.

Results reported as:

N/N Normal - no copies of the DM mutation
N/DM 1 copy of the DM mutation
DM/DM 2 copies of the DM mutation; dog may develop DM disease

References:

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. [PubMed: 19188595]

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. [PubMed: 18196743]

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. [PubMed: 22542607]

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, 28(2):515-521.

 

Hemophilia A/Factor VIII Deficiency

Introduction

Hemophilia A is an inherited bleeding disorder caused by a deficiency of coagulation factor VIII (F8), an essential protein required for normal blood clotting. Affected dogs have variable presentation of the disease, with mild to moderate bleeding being observed. Additionally, affected dogs may bruise easily or have extended periods of bleeding following trauma. Frequent nosebleeds and stiffness may also indicate F8 deficiency resulting from excessive internal bleeding after damage to muscles and joints. While bleeding is occasionally severe enough to result in death, most affected dogs have a normal lifespan. Variable presentation coupled with a lack of observable incidents with bleeding often results in this condition going undetected until a dog has a surgical procedure or severe trauma.

Two independent mutations in the Factor VIII gene result in German Shepherd Dog F8 deficiency: c.98G>A (reported as HEMA-1) and c.1643G>A (reported as HEMA-2). In Boxers, F8 deficiency results from a c.1412C>G mutation in exon 10 (reported as HEMAbx). The disease is inherited in an X-linked recessive fashion. Females with two defective copies will show disease. Clinical signs are absent in females with one normal and one affected gene (carriers). Males have only one X chromosome. If the inherited allele is affected, males will show disease. If the inherited allele is normal, males do not have the disease.

The Veterinary Genetics Laboratory offers genetic tests for Hemophilia A. Test results assist veterinarians with diagnosis of F8 deficiency and help breeders identify carriers among breeding females and affected breeding males to avoid mating pairs that can produce affected dogs. When a carrier female is bred to a normal male, all female puppies will be normal but 50% of them will be carriers.  Among male puppies from this type of cross, 50% will be normal and 50% will be affected.

Testing recommended for: German Shepherd Dog, Shiloh Shepherd, White Shepherd Dog, Boxer, (This test does not detect the causative mutations for F8 deficiency in Old English Sheepdog, Irish Setter or Miniature Schnauzer)

Results reported as:

N/N

Normal female - no copies of F8 mutations.

N/HEMA*

Carrier female - 1 copy of the HEMA* mutation

HEMA/HEMA*

Affected female - 2 copies of the HEMA* mutation

N

Normal male - no copies of the F8 mutations

HEMA*

Affected male - 1 copy of the HEMA* mutation

 

 

 

* Report will specify HEMA-1, HEMA-2 or HEMAbx according to breed and mutation present.

References:

Christopherson PW, Bacek LM, King KB, Boudreaux MK. (2014) Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog. Vet Clin Pathol 43:312-316.
Mischke R, Wilhelm Ch, Czwalinna A, Varvenne M, Narten K, von Depka M. (2011) Canine haemophilia A caused by a mutation leading to a stop codon. Vet Rec 169:496b.

 

Canine Hyperuricosuria
Introduction

Hyperuricosuria (HUU) means elevated levels of uric acid in the urine. This trait predisposes dogs to form stones in their bladders or sometimes kidneys. These stones often must be removed surgically and can be difficult to treat. HUU is inherited as a simple autosomal recessive defect. A mutation in exon 5 of the gene Solute carrier family 2, member 9 (SLC2A9) has been found to be associated with hyperuricosuria in dogs. HUU can occur in any breed but is most commonly found in the Dalmatian, Bulldog and Black Russian Terrier. While traditional Dalmatians are homozygous for HUU (HU/HU), the introduction of “low uric acid” dogs, derived from Dalmatian x Pointer backcrosses, into the purebred gene pool has provided a means for breeders to reduce incidence of the disease and maintain the breed characteristics. Normal (N/N) and carrier (N/HU) Dalmatians are now present in the breed, and trace to the backcross lineage.

A DNA test for the SLC2A9 mutation can determine the genetic status of dogs for HUU. Dogs that carry two copies of the mutation will be affected and susceptible to develop bladder/kidney stones. The SCL2A9 mutation is not the sole cause of urate bladder stones in dogs. Other factors such as liver disease and diet need also be considered in clinical evaluation.

Detailed Hyperuricosuria Information

The VGL offers a DNA test for hyperuricosuria to assist owners and breeders in identifying affected and carrier dogs. The test uses DNA collected from buccal swabs thus avoiding invasive blood collection. Breeders can use results from the test as a tool for selection of mating pairs to avoid producing affected dogs. The test is offered to all breeds, including American Pitbull Terrier, American Staffordshire Terrier, Australian Shepherd, Black Russian Terrier, Bulldog, Catahoula Leopard Dog, Dalmatian, Danish-Swedish Farmdog, German Hunting Terrier, German Shepherd, Giant Schnauzer, Jack Russel/Parsons Terrier, Kromfohrländer, Labrador Retriever, Lagotto Romagnolo, Large Munsterlander, South African Boerboel, Spaniel de Pont-Audemer, Swedish Vallhund, Vizsla and Weimaraner.

Results reported as:

N/N No copies of hyperuricosuria mutation; dog is normal
N/HU 1 copy of hyperurisosuria mutation; dog is normal but is a carrier
HU/HU 2 copies of hyperuricosuria mutation; dog is affected and susceptible to develop bladder/kidney stones.

Research Hyperuricosuria is ongoing to determine other breeds with this problem.  We recommend testing any dog that has formed kidney or bladder stones composed of urate or uric acid. If the dog has the mutation then treatment modalities for Dalmatians can be used to treat the dog.

References:

Bannasch D, N Safra, A Young, N Karmi, RS Schaible and GV Ling (2008) Mutations in the SLC2A9 Gene Cause Hyperuricosuria and Hyperuricemia in the Dog. PLoS Genetics 4(11): e1000246. doi:10.1371/journal.pgen.1000246

Karmi N, EA Brown, SS Hughes, B McLaughlin, CS Mellersh, V Biourge, and DL Bannasch (2010) Estimated Frequency of the Canine Hyperuricosuria Mutation in Different Dog Breeds. Journal of Veterinary and Internal Medicine 2010;24:1337–1342.

X-linked Hypohidrotic Ectodermal Dysplasia/Anhidrotic Ectodermal Dysplasia

Introduction

X-linked hypohidrotic ectodermal dysplasia (XHED) is an inherited disorder that has been reported in several breed and mixed-breed dogs. Affected pups are born lacking hair on the forehead and back near the tail. Pups have a high frequency of eye infections prior to opening. Both teeth and secondary hair are either absent or abnormal. The mechanism for clearing matter from the respiratory tract (mucociliary clearance) is diminished, resulting in an increased susceptibility to pulmonary infections. Clinically, a lack of glands in affected dogs has been noted, including bronchial, tracheal, esophageal and sweat glands.

Except for the German Shepherd Dog, the molecular basis of this defect in different breeds is unknown and likely results from different mutations. In German Shepherd Dogs, XHED deficiency results from a c.910-1G>A (reported as XHEDgs) mutation in the intron 8 splice acceptor site of ectodysplasin A (EDA) gene resulting in abnormal protein production. EDA is involved in the morphogenesis of hair follicles and tooth buds. The disease is inherited in an X-linked recessive fashion. Females with two copies of the affected allele will show disease. Clinical signs are absent in females with one normal and one affected gene (carriers). Males have only one X chromosome. If the inherited allele is affected, males will show disease. If the inherited allele is normal, the dog does not have the disease.

The Veterinary Genetics Laboratory offers genetic tests for the German Shepherd form of XHED. Test results assist veterinarians with diagnosis of XHED and help breeders identify carrier females among breeding stock to avoid mating pairs that can produce affected dogs. When a carrier female is bred to a normal male, all female puppies will be normal but 50% of them will be carriers.  Among male puppies from this cross, 50% will be normal and 50% will be affected.

Testing recommended for: German Shepherd Dogs

Results reported as:

N/N

Normal female - no copies of the XHEDgs mutations.

N/XHEDgs

Carrier female - 1 copy of the XHEDgs mutation

XHEDgs/XHEDgs

Affected female - 2 copies of the XHEDgs mutation

N

Normal male - no copies of the XHEDgs mutations

XHEDgs

Affected male - 1 copy of the XHEDgs mutation

 

 

 

 

References:

Casal ML, Scheidt JL, Rhodes JL, Henthorn PS, Werner P. (2005) Mutation identification in a canine model of X-linked ectodermal dysplasia. Mamm Genome 16:524-31.

Casal ML, Mauldin EA, Ryan  S, Scheidt JL, Kennedy J, Moore PF, Felsburg PJ. (2005) Frequent respiratory tract infections in the canine model of X-linked ectodermal dysplasia are not caused by an immune deficiency. Vet Immunol Immunopathol 107:95-104.

Mucopolysaccharidosis VII

Introduction

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease characterized by accumulation of glycosaminoglycans (amino sugars) within cells. Glycosaminoglycans are found in cells involved with development of bone, cartilage, tendons, corneas, skin and connective tissue, and in fluid that lubricates joints. Under normal conditions of cell metabolism, these amino sugars are broken down into simpler sugars by the beta-glucuronidase enzyme encoded by the gene β- glucuronidase (GUSB). Mutations in the GUSB gene disrupt production or activity of this enzyme leading to an accumulation of amino sugars that causes permanent cell damage. MPS VII disease has an early onset and is progressive. By one month of age, affected pups typically show shortened broad faces, low-set ears, and broad chests relative to unaffected littermates. By two months of age, corneal clouding is observed and differential development is apparent with affected dogs being roughly half the size of unaffected siblings. As the disease progresses, standing becomes difficult and joints become swollen and are easily dislocated. Additional clinical signs include cardiac abnormalities, tracheal narrowing, and glycosaminoglycans in the urine.

Two independent, breed-specific mutations in the GUSB gene result in MPS VII disease: c.866C>T in Brazilian Terriers (reported as MPS7bt) and c.497G>A in German Shepherd Dogs (reported as MPS7gs).  In both cases, the disease is inherited in an autosomal recessive fashion, which means that males and females are equally affected and that two copies of the defective gene are needed to cause MPSVII. Dogs with one normal and one affected gene (carriers) are normal and show no signs of the disease.

The Veterinary Genetics Laboratory offers genetic tests for MPS VII. Test results assist veterinarians with diagnosis of MPS VII and help breeders identify carriers among breeding stock to avoid producing affected dogs. Matings between carriers are expected to produce 25% of affected puppies.

Testing recommended for: Brazilian Terrier, German Shepherd Dog

Results reported as:

N/N

Normal - no copies of the MPSVIImutation

N/MPS7*

Carrier - 1 copy of the MPSVII mutation

MPS7/MPS7*

Affected - 2 copies of the MPSVIImutation

*Report will specify MPS7bt or MPS7gs according to breed and mutation present.

References:

Hytönen MK, Arumilli M, Lappalainen AK, Kallio H, Snellman M, Sainio K, Lohi H. (2012) A novel GUSB mutation in Brazilian terriers with severe skeletal abnormalities defines the disease as mucopolysaccharidosis VII. PLoS One 7:e40281.

Ray J, Bouvet A, DeSanto C, Fyfe JC, Xu D, Wolfe JH, Aguirre GD, Patterson DF, Haskins ME, Henthorn PS. (1998) 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.

Renal cystadenocarcinoma and nodular dermatofibrosis

Introduction

Renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is an inherited cancer in German Shepherd Dogs. The disease has late onset and is progressive. Affected animals develop multiple firm nodules (dermatofibrosis) in the skin typically by 6 years of age. They also develop bilateral, multifocal tumors (cystadenocarcinoma) in the kidney although the timing and rate of growth is varied.

RCND in the German Shepherd Dog breed results from a mutation in exon 7 (c.764A>G) of the folliculin (FLCN) gene. The disease is inherited in an autosomal dominant fashion, which means that males and females are equally affected and that a single copy of the defective gene will cause disease. Animals with two defective copies have not been identified suggesting this genotype is incompatible with life.

The Veterinary Genetics Laboratory offers genetic tests for RCND. Test results assist veterinarians with diagnosis of RNCD and help breeders identify affected dogs among breeding stock to avoid producing affected puppies. Matings between two dogs that have one copy each of the RCND mutation are expected to produce only 25% of normal puppies with no copies of the mutation. This mating may also result in potential loss of embryos with two copies of the RCND mutation as it appears to be homozygous lethal.

Testing recommended for: German Shepherd Dog

Results reported as:

N/N

Normal - no copies of the RCNDmutation

N/RCND

Affected - 1 copy of the RCND mutation

RCND/RCND

Affected - 2 copies of the RCNDmutation (may not be viable)

References:

Lingaas F, Comstock KE, Kirkness EF, Sørensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA. (2003) 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 12:3043-3053.

 

 
Veterinary Genetics Laboratory, Tel 530-752-2211, Email VGL