Genetic Testing: Expectations, Opportunities and Limitations
World Small Animal Veterinary Association Congress Proceedings, 2017
Merete Fredholm, DVM, PhD, DrVetSci
Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark


All mammals (including humans) carry a number of recessive disease genes, and disease-predisposing genes which can result in the development of inherited diseases. The recessive disease genes result in disease when they occur in homozygous combinations, and the disease-predisposing genes result in disease when they occur in inappropriate constellations, or when a given individual carries too many of them. In populations with limited genetic variation, the risk of developing homozygosity and/or accumulation of disease-predisposing genes is higher compared to the risk in populations with large genetic variation.

The genomes of the dog breeds that we maintain today have been 'shaped' by two bottlenecks, the last of which occurred approximately 200 years ago when the modern breeds were established through systematic breeding within closed populations. This has resulted in the establishment of around 400 distinct dog breeds, each with individual characteristics with respect to appearance, abilities, and behavioral predispositions. The systematic breeding within closed population, however, also implies that our dog breeds represent populations with limited genetic variation and this, in turn, requires that breeding schemes take into consideration that further reduction of genetic variation has to be avoided.

The great progress made within the area of molecular genetics during recent years has enabled researchers to study the molecular background for inherited diseases and a large number of genetic tests have been established. Genetic tests with high sensitivity and specificity can be used to circumvent loss of genetic variation; however, as discussed below, there are a number of pitfalls with genetic testing which need to be taken into consideration to avoid exclusion of perfectly healthy dogs from breeding.

Mendelian Inherited Diseases

According to the database Online Mendelian Inheritance in Animals (OMIA:, there are currently 225 traits/disorders for which the key mutation is known. Many of the identified key mutations are mutations underlying recessive diseases. Most of the genetic tests developed based on knowledge about the underlying mutation provide efficient tools both to prevent production of affected puppies and to prevent loss of genetic variation. This is accomplished by allowing breeding with carrier dogs to dogs tested free for the mutation. To exemplify this breeding strategy: In 2006 a mutation in choline O-acetyltransferase (CHAT) was shown to be the causative mutation for congenital myasthenic syndrome in old Danish pointing dogs.1 This dog breed is a numerically small breed with a production of only around 100 puppies per year, and limited genetic variation (it was reconstructed based on a limited number of founders around 1950). All dogs used for breeding have been genotyped for the mutation until recently and no affected puppies have been produced since the initiation of genotyping. Although the allele frequency of the disease allele was low in the population in 2006 when the mutation was detected, carrier dogs have been used for breeding. The last carrier dog was genotyped in 2011 and presently all dogs used for breeding are free due to the genotypes of parents. Thus, the mutation has been removed from the population over a 6-year period.

The large enthusiasm with respect to establishing and using genetic testing has, however, also let to introduction of tests that are insufficiently validated. One such example is the test established for genotyping of collie eye anomaly (CEA) in, among other breeds, collies and Shetland sheepdog.2 A study of the association between the clinical diagnosis and the genetic diagnosis in the Danish populations of the two breeds has shown that the test is only predictive in Shetland sheepdog.3 Thus, although the mutation originally presented by Parker and colleagues (2016) was assumed to be the causative mutation, the study in the Danish populations indicates that the target of the genetic test is a marker segregating with the disease in some populations.

Another example of an insufficiently validated test is the test developed for genotyping of ichthyosis (generalized excessive scaling and hyperpigmentation) in the golden retriever.4 A follow-up study conducted in 30 dogs, which had been genotyped to be homozygous for the mutation, showed that only few of the dogs had problems with dandruff.5 This could indicate either that the disease is influenced by other genes and/or that environmental factors play a large role in the development of the disease.

Quantitative Diseases

Quantitative diseases are, as mentioned, caused by accumulation of disease-predisposing genes. Since several genes are involved in the development of these diseases and since they are also often under the influence of environmental factors, it is more difficult to establish genetic testing for them. In spite of this, we will undoubtedly see more tests developed in the future. Recently, a test aimed at predicting the probability for developing hip dysplasia in Labrador retriever was established.6 The test has been validated in 126 Danish Labrador retrievers with radiographic hip scores and estimated breeding values registered in the Danish Kennel Club. No significant statistical correlation between phenotypic scores and genotypic predisposition was detected.7

Conclusions and Future Perspectives

Genetic testing is an extremely valuable tool to combat inherited diseases. However, three important aspects have to be taken into consideration before a specific test can be recommended to be included in a breeding scheme: (i) unless the test has unambiguously been proven to target the causative mutation, it has to be validated in the population at hand; (ii) the relative impact on welfare of the disease which is targeted has to be considered in the context of the general health status of the breed; (iii) considerations concerning selection intensity in order to avoid further reduction of genetic variation have to be made.

With the progress and decreasing costs in regard to full genome sequencing, there will be a still growing number of tests on the market. Since dog owners and breeders show great enthusiasm with regard to genetic testing, genetic counseling is of great importance. Hence, there will be a future demand for veterinarians specialized within the area of Clinical Genetics.


1.  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. Journal of Heredity. 2007;98:539–543.

2.  Parker HG, Kukekova AV, Akey DT, Goldstein O, Kirkness EF, Baysac KC, et al. Breed relationships facilitate gene-mapping studies: a 7.8-kb deletion cosegregates with Collie eye anomaly across multiple dog breeds. Genome Research. 2007;17(11):1562–1571.

3.  Fredholm M, Larsen RC, Jönsson M, Söderlund MA, Hardon T, Proschowsky HF. Discrepancy in compliance between the clinical and genetic diagnosis of choroidal hypoplasia in Danish rough collies and Shetland sheepdogs. Animal Genetics. 2016, doi: 10.1111/age.12405.

4.  Grall A, Guaguère E, Planchais S, Grond S, Bourrat E, Hausser I, et al. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nature Genetics. 2012;44(2):140–147.

5.  Jensen CN. Ichthyosis in the golden retriever: variation of clinical manifestation and breeding aspects in golden retrievers that are homozygous for the PNPLA-1 mutation. Master thesis, 2014, University of Copenhagen.

6.  Bartolomé N, Segarra S, Artieda M, Francino O, Sánchez E, Szczypiorska M, Casellas J, Tejedor D, Cerdeira J, Martinez A, Velasco A, Sánchez A. A genetic predictive model for canine hip dysplasia: integration of Genome Wide Association Study (GWAS) and candidate gene approaches. PLoS One. 2015, doi: 10:e0122558.

7.  Bank A, Ström A. Validation of the Dysgen Hip Dysplasia DNA test in the Danish population of Labrador Retrievers. Master thesis, 2016, University of Copenhagen.


Speaker Information
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Merete Fredholm, DVM, PhD, DrVetSci
Faculty of Health and Medical Sciences
University of Copenhagen
Frederiksberg C, Denmark