GENETIC DISEASE TESTING
Thanks to the efforts of genetic researchers, many canine genetic disease tests are commercially available (Table 1 (PDF)). Single gene mutations have been identified as the cause of most of these diseases. An understanding of the different inheritance
patterns is required when recommending testing and in interpreting the results. Mutated genes can be expressed in a dominant
or recessive manner and can be located on autosomal or sex chromosomes. All of these factors affect how the mutation impacts
Most of the causative genes identified are inherited in an autosomal recessive manner. Remembering that most cells have two
copies of each chromosome and, thus, two copies of each gene, an autosomal recessive disease requires two copies of the defective
gene for disease to occur. A carrier of an autosomal recessive disease is an animal that has one normal gene and one defective
gene (heterozygous) with no disease signs (Figure 1). This animal can pass the defective gene to its offspring, and, if mated with another carrier, the offspring will have a
25% chance of being homozygous for the mutation and suffering from the disease. Without genetic testing, prospective identification
of mutation carriers involves progeny testing from matings with known carriers—a difficult task. Generally, results of genetic
testing for autosomal recessive traits are reported as "negative" or "normal" (no mutation on either gene), "carrier" (one
mutation), or "positive" or "affected" (both copies of the gene are mutated).
Figures 1 and 2: Examples of Mendelian genetics
Many other types of inheritance patterns exist, including autosomal dominant diseases, X-linked diseases, mutations with incomplete
penetrance, and polygenic diseases. Autosomal dominant diseases have no carrier state. If one copy of the mutation is present,
then the associated disease is present. For example, dominant progressive retinal atrophy will be present in a dog with just
one copy of the mutated RHO gene. Sex-linked traits occur when the mutated gene is located on a sex chromosome and can be recessive or dominant (Figure 2). An X-linked recessive mutation would affect more males than females since males have only one X chromosome, with females
requiring two copies of the mutation to be affected, as is the case of hemophilia B in bull terriers. An X-linked dominant
mutation would typically affect more females than males.
Autosomal dominant mutations with mixed penetrance are more complicated. In this type of inheritance pattern, the variable
disease expression is thought to depend on other genetic or environmental risk factors. An example of this type of inheritance
pattern is hereditary cataracts in Australian shepherds.6 One copy of the mutated gene results in a greater risk for cataract development but does not guarantee disease will develop.
Conversely, a few dogs in the study did not carry the mutation but developed cataracts. This genetic test may be most useful
to breeders of Australian shepherds selecting to decrease risk of this disease in their lines.
Some disorders have an even more complex genetic etiology in which molecular variation in many genes contributes to disease.
Patterns of such polygenic inheritance are commonly studied by genetic marker mapping studies in which the typing of hundreds
to thousands of genetically variant DNA markers spaced across the entire genome are used to derive correlations between the
genetic markers and disease. DNA markers have been identified that are associated with certain diseases for which the causative
gene is unknown. These marker tests carry a higher risk of inaccuracy since the mutant gene itself cannot be directly tested,
but they can still provide valuable information.
One example is quantitative trait loci (QTL) studies, which have been performed to help unravel the genetic basis of canine
hip dysplasia.7-9 In one study, an affected breed, the Labrador retriever, was crossed with a resistant breed, the greyhound (Figure 3).7 Three generations of offspring were evaluated for hip dysplasia by using radiographic techniques and then typed by using
known genetic markers that differ between Labrador retrievers and greyhounds. This effort led to the identification of 12
Labrador retriever QTL in the crossbred offspring that correlated with the presence of hip dysplasia.
More recent studies have surveyed hundreds of German shepherds and Labrador retrievers for radiographic evidence of hip dysplasia
and then looked for the genetic markers that correlate with disease expression.8,9 These studies have found QTL that overlap with those in the Labrador retriever-greyhound study as well as additional novel
QTL. However, QTL analysis is based on DNA marker associations. In this way, they are signposts of genetic regions that harbor
the genes that cause disease. The next step is to identify the specific mutated genes that are responsible for the genetic
It is not always clear which type of test is being offered (markers or specific genes) as some genetic testing providers guard
the specifics of their testing as proprietary. When provided, statistical relevance of the test to the disease offers you
some assurance of the test's reliability and clinical worth.
Finally, a single clinical disease may be caused by mutations in different genes in different breeds. For example, progressive
retinal atrophy can be caused by any one of 15 mutations in 11 genes in 34 breeds.10 Two unrelated mutations can also occur in the same gene. In retinal cone degeneration, the CNGB3 gene has a missense mutation in German shorthaired pointers and a deletion mutation in Alaskan malamutes. These mutations
arose spontaneously and independently of each other in these two breeds but cause the same clinical disease. Given these variations,
you should be aware that certain genetic tests are recommended only for specific breeds. The genetic test should be validated
for the particular breed being tested.
Most of the disease-causing mutations listed in Table 1 (PDF) have been published in scientific journals and are referenced if applicable. Several organizations provide information on
available genetic tests through their websites, such as the Orthopedic Foundation for Animals (
http://www.offa.org/), the Canine Genetic Diseases Network (
http://www.caninegeneticdiseases.net/), and the National Human Genome Research Institute (NHGRI) Dog Genome Project (http://research.nhgri.nih.gov/dog_genome/). Additional resources for available tests include veterinary genetic test providers, such as OptiGen and VetGen.