Dilated Cardiomyopathy - What is this test telling and should I be worried?

Dilated Cardiomyopathy (DCM) is a severe hereditary disorder present in Doberman Pinschers and other breeds that ultimately leads to heart failure and sudden death.

In 2012, a group of scientists including lead author Dr. Kathryn Meurs published an article reporting a mutation associated with increased risk for DCM in a cohort of Doberman Pinchers in America. This mutation is located in the PDK4 gene (Meurs et al., 2012), which encodes a protein of the mitochondrion, the cells power source - a vital part of the cell in which malfunctions are often disastrous. However, a year after the American discovery, a European group led by Dr. Tosso Leeb screened a large amount of Dobermans and dogs of other breeds from Germany and Great Britain and was unable to replicate the previous results. In this new study, the mutation was not associated  with DCM, after a statistical analysis in which the question was whether the mutation was found more frequently in affected Dobermans than in healthy ones or not (Owczarek-Lipska et al., 2013). Additionally the mutation was shown to be common in the other breeds, which makes it less likely that it is a direct cause for the disease. These results also correspond well with our own experiences from comprehensive MyDogDNA panel screening: We similarly observe the DCM mutation present in several breeds at a high frequency.

Against this background, it is clear that the proposed mutation for DCM described by Meurs and colleagues is not the direct cause for the onset of the disease in any breed, and it is likely to be completely harmless in several breeds.  Having said that, testing for the mutation still has a high value at least in the limited Doberman population it was found in, that is Dobermans of American origin. In general, there are often exceptions to the basic rules of genetics like the one described here. In this case, the geneticist would call it incomplete penetrance: Genetically affected, or carrier dogs that have this DCM mutation in their genome might never develop the condition. This means that there are likely several other genetic factors, and possibly environmental factors  that jointly influence DCM onset in a complex manner. To evaluate the role of the PDK4 gene in DCM it would be important to assess the molecular machinery it acts in.

In DNA-testing, how do we then interpret a test result for a mutation like this?

To put it simply, an “affected” test result for a dog of a breed other than Doberman Pinscher is in our opinion not a cause to worry. No one has yet proven that the tested mutation has an effect in any other breed. For this reason, we do not recommend omitting any dogs from breeding based on this finding.

If a Doberman Pinscher is tested “affected”, additional information about the dog’s origin is needed to interpret the result. Remember that a statistical correlation between DCM and the tested mutation has only been proven in Dobermans of American origin. In American Dobermans, an “affected” result indicates that the dog has an approximately 7-fold increased risk for DCM, compared to dogs tested “clear” (Meurs et al., 2012). In European Dobermans, a genetically “affected” result has not been shown to have any effect on DCM risk (Owczarek-Lipska et al., 2013). Therefore, in our opinion, an “affected” result in a Doberman of European origin is not a cause for worry based on current knowledge, and we do not recommend omitting dogs from breeding based on this finding.

In conclusion, DCM is likely a disorder with a complex genetic origin. Further research is needed to understand the role of genetic variation in the PDK4 gene in influencing DCM onset. The MyDogDNA database offers an easy means of identifying dogs carrying the putative mutation and thereby conducting a follow up study addressing whether the mutation increases the risk for DCM in other populations and breeds besides American Dobermans.

Currently, the DCM test offered by others and us only assesses one potential risk factor for DCM, and it is important to understand its limitations in predicting disease onset (i.e., it has a demonstrated effect only in one sub-population of one breed and incomplete penetrance even in that population). Genetic information of this nature should be critically interpreted and applied with caution to breeding programs in order to avoid breeding schemes that unnecessarily decrease genetic diversity.

 

REFERENCES

Meurs KM, Lahmers S, Keene BW, White SN, Oyama MA, Mauceli E, Lindblad-Toh K. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher. Hum Genet 2012; 131(8):1319-1325.

Mausberg TB, Wess G, Simak J, Keller L, Drögemüller M, Drögemüller C, Webster MT, Stephenson H, Dukes-McEwan J, Leeb T. A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers. PLoS One 2011;6(5):e20042.

Owczarek-Lipska M, Mausberg TB, Stephenson H, Dukes-McEwan J, Wess G, Leeb T. A 16-bp deletion in the canine PDK4 gene is not associated with dilated cardiomyopathy in a European cohort of Doberman Pinschers. Anim Genet 2013; 44(2):239.