Jerold S. Bell, DVM
Dept. of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA
Genetic diseases common in mixed-breed and purebred dogs are typically associated with evolutionarily ancient disease-liability genes. These emerged prior to the separation of breeds and are dispersed in the domestic dog genome. Pedigreed breeds may have varied incidence of disease, depending on the frequencies of liability genes in their gene pools. The hallmark of inherited disease is predictability of onset and progression. Recognizing predictable triggers and modifying factors that influence the expression of genetic disorders can help improve diagnosis, treatment, and control.
Insurance claims and centralized hospital databases monitor the most frequent disease presentations, which helps veterinarians understand the most frequent genetic diseases. The most frequent conditions are complexly inherited and involve combinations of multiple genes and environmental factors. Genetic diseases should be recognized in practice because they must be treated as chronic illnesses - not episodic diseases.
Allergic Skin Disease
Manifestations of allergic skin disease (e.g., chronic inflammatory otitis, recurrent hot spots, pruritus) are the most frequent disease presentations in clinical practice. These presentations are commonly seen in mixed-breed and purebred dogs, with some breeds having a higher incidence than others. A study of atopic dermatitis in Golden and Labrador Retrievers showed heritability (i.e., percent of liability due to genetic influence) at 47%, which also indicates a significant environmental contribution. A molecular genetic study of atopic dermatitis in German Shepherd Dogs identified an associated segment of chromosome 28.
No genetic-liability tests are available. Predictable seasonality can be recognized in 15% to 62% (median, 30%) of allergic dogs with chronic presentations. For these patients, interventional measures to manage pruritus should be prescribed before it progresses to clinical disease.
Canine Hip Dysplasia
Hip dysplasia, which occurs across all mixed-breed and purebred dogs, is the most common inherited musculoskeletal disorder. Of all dogs for which radiographs are submitted to the Orthopedic Foundation for Animals (www.ofa.org), 14.6% are rated as dysplastic. This is a low estimate, as clinically apparent cases may not be submitted for evaluation. Small dogs with hip dysplasia usually do not show the pain and discomfort seen in larger dogs, demonstrating a size - weight relationship to clinical presentation. Radiographic diagnosis is made through ventrodorsal view or distraction index.
Palpable hip laxity can predict hip dysplasia and later osteoarthritic changes. A gentle Ortolani procedure during puppy examinations and palpation for hip laxity under anesthesia during neutering should be performed. Dogs with severe laxity identified at an early age may benefit from interventional surgery.
Estimated breeding values and genotypic breeding values based on DNA marker panels are being experimentally developed to assist with selection for hip normalcy. Breeders should select for familial breadth and depth of normalcy as seen in vertical pedigrees.
Brachycephalic Obstructive Airway Syndrome
Brachycephalic obstructive airway syndrome (BOAS) is a disorder of breathing difficulty in short-snouted and “bully” breeds. Breeds with the highest prevalence include Bulldogs, French Bulldogs, and Pugs. BOAS occurs because of a mismatch in the proportions of the skull and soft tissue in the nose and pharynx. Clinical signs include dyspnea, exercise intolerance, heat intolerance, abnormal and increased respiratory noise, cyanosis, syncope, and death. In one study, 16.7% of high-risk dogs died of respiratory failure at an average of 8.6 years of age.
This syndrome includes stenotic nares, an elongated soft palate, everted laryngeal saccules, laryngeal collapse, and/or a hypoplastic trachea. Brachycephalic dogs may present with facial skin fold dermatitis and corneal ulceration. For dogs experiencing significant morbidity, corrective surgery can include rhinoplasty for stenotic nares, soft palate resection, and laryngeal saccule removal. Breeders should select for dogs that do not show signs of BOAS and that have a defined muzzle, a normal-diameter trachea (ratio of lumen diameter at the thoracic inlet to the width of the proximal third rib should be ≥2 on a lateral radiograph), and wide nostrils.
Myxomatous Mitral Valve Disease
Myxomatous mitral valve disease (i.e., mitral valve endocardiosis) is primarily seen in older toy breeds and small dogs. For some breeds (e.g., Norfolk Terrier, Cavalier King Charles Spaniel), it may lead to heart disease at an average age of 6.25 years. As this is beyond breeding age, some Cavalier King Charles Spaniel clubs have established a generational breeding control program in which dogs are only bred if both parents are free of a murmur and Doppler evidence of mitral regurgitation. When this program is applied, the frequency of this disorder has decreased.
Cranial Cruciate Ligament Rupture
Cranial cruciate ligament rupture is a common traumatic injury. Although it is not typically considered a hereditary disease, studies show increased risk in Rottweilers, West Highland White Terriers, Golden Retrievers, Yorkshire Terriers, Staffordshire Bull Terriers, and some mixed-breed dogs. Studies of cranial cruciate ligament rupture in Newfoundlands show 27% heritability. Genetic predisposing factors for rupture may include issues with ligament extracellular matrix metabolism, degeneration and/or inflammation. Other predisposing factors may involve biomechanical and conformational variations (e.g., bone length, stifle angulation, tibial plateau variation, or narrowed distal femoral intercondylar notch).
Patellar Luxation is a complexly inherited disorder that causes the kneecap to pop out of the trochlea either medially or laterally. It is more common in the small stature breeds; however, several larger breeds also have a high incidence of the disorder. Patella luxation can be subclinical or can cause pain, instability and arthritic changes. Weight control is an important factor in decreasing morbidity. Affected dogs usually progress from Grade 1 (patella laxity) to Grade 4 (permanent fixation out of the trochlea) over time. Breeders must use breadth and depth of pedigree normalcy to select against this disorder.
While all cancers are due to mutations present in tumor cells, some cancers are perceived to be spontaneous or environmental, and some due to inherited predisposing influences. The most frequently diagnosed inherited canine cancers are; lymphoma/lymphosarcoma, hemangiosarcoma, mast cell tumor and osteosarcoma. Other lower frequency cancers with genetic predispositions are malignant melanoma, squamous cell carcinoma, mammary tumors, transitional cell carcinoma, and histiocytic sarcoma.
Cancer susceptibility genes include tumor suppressor genes involved in cell surveillance (removing “non-self” cells with mutations) and oncogenes that can cause malignant transformation of cells. Many abnormal genes as well as chromosomal anomalies are identified in tumor tissues, but most of these findings do not correlate to “cancer causing genes” in the normal (pre-cancer) genotype. Current research has identified genetic markers or gene variants that are present at a higher frequency in dogs diagnosed with cancer. Time will tell whether these findings will translate to screening tests for genetic cancer susceptibility.
Retained testicles are seen frequently in mixed and purebred dogs with a reported 6.8% prevalence. It can present as unilateral or bilateral. The location of the retained testicle can be abdominal or subcutaneous.
Testes should normally be present in the scrotum by 8 weeks of age. Cryptorchidism is a complexly inherited sex-limited trait where both males and females inherit the trait, but only males can express it (similar to milk production in females). Therefore, genetic control must include selective pressure against female close relatives of affected males. Late descending testicles (up to 14 weeks of age) are an expression of the disorder, so this trait should also be selected against.
Hypothyroidism is a frequently reported disorder of purebred and mixed-breed dogs. It is caused by an autoimmune thyroiditis where thyroglobulin autoantibodies (TgAA) slowly destroy the thyroid hormone producing tissue. Thyroid screening shows 6.3% of blood samples from mixed and purebred dogs testing positive for TgAA.
At question is what percentage of dogs with measurable TgAA progress to end-stage clinical hypothyroidism, as this has not been documented in any studies. Resting T4 measurements are a poor indicator of primary hypothyroidism, as many dogs with non-thyroid illness have low T4 levels. Compounding this is that there are many thyroid hormone responsive conditions such as; obesity, lethargy, and poor hair coat. While autoimmune thyroiditis certainly does exist as a hereditary disease in dogs, it may be an improperly or over-diagnosed disorder.
Many dogs develop slowly progressive cataracts as they get older, and it is likely that all spontaneous cataracts have hereditary components. Eye screening programs in Germany have shown a reduction in cataracts in Dachshunds from 8.7% in 1993 to 3.1% in 2006. A testable genetic mutation (HSA1) causes autosomal recessive early-onset cataracts by 6 months with complete opacity by 2 years of age in the Boston Terrier, Staffordshire Bull Terrier, and French Bulldog breeds. A different mutation in the same gene causes autosomal dominant early-age cataracts in the Australian Shepard breed. There are many documented breed-related inherited cataracts, and some breeds have more than one inherited cataract; differentiated by age of onset, progression, and lens location. Other causative mutations have not yet been discovered.
Other Common Genetic Disorders
Other common disorders include; non-struvite bladder stones, elbow dysplasia, hepatic shunts, epilepsy, glaucoma, deafness, blindness, renal dysplasia, and Addison’s disease. Common Mendelian disorders with genetic tests include; the prcd form of progressive retinal atrophy, mdr1-related drug sensitivity, arrhythmogenic right ventricular cardiomyopathy in Boxers and Boxer crosses, von Willebrand ‘s disease, and a liability gene for degenerative myelopathy.
The WSAVA Canine and Feline Hereditary Disease (DNA) Testing website (http://research.vet.upenn.edu/WSAVALabSearch) (VIN editor: Link not accessible) is an excellent source for DNA tests, lists of susceptible breeds and testing laboratories.
Dogs affected by genetic disorders should not be selected for breeding. Because most of these genetic diseases are complexly inherited, genetic risk for carrying disease-liability genes should be based on knowledge of clinical disease or normalcy in first-degree relatives of prospective breeding dogs. This can be facilitated through on-line health registry databases. Carriers of testable recessive disease-liability genes can be bred with normal-testing mates and replaced for breeding with normal-testing offspring. Dogs with testable dominant disease-liability genes should be replaced for breeding with normal-testing relatives.