Dilated cardiomyopathy (DCM) in Doberman

Dilated cardiomyopathy (DCM) is the second most common heart disease in dogs. So far, four genetic variants associated with the development of DCM in the Doberman breed have been detected. However, it is likely that there are more of these variants. The first two variants (DCM1 and DCM2) have been discovered in the American Doberman population, the other two variants (DCM3 and DCM4) in the European Doberman population. The disease is accompanied by symptoms such as cardiac arrhythmias, myocardial dysfunction and subsequent congestive heart failure. In Dobermans, the disease manifests itself in adulthood. The course of the disease, the age of onset and the rate of progression vary not only between individuals but also between sexes. For example, in males the first symptoms of DCM appear at a younger age than in females. The estimated prevalence of dilated cardiomyopathy in Dobermans is 58.2% (Wess et al. 2010). According to the statistics, the Doberman breed ranks first among the breeds affected by dilated cardiomyopathy.

The first genetic variant of DCM1 is caused by a 16 bp deletion detected in the PDK4 gene. The PDK4 gene is responsible for regulating energy metabolism by phosphorylating pyruvate dehydrogenase in mitochondria. This large deletion causes a reduction in phosphorylation capacity, which is essential for the functioning of mitochondrial energy metabolism. In dogs with a defect in the PDK4 gene, very severe up to pathological changes occur within the mitochondria. Insufficient functioning of energy metabolism in the mitochondria is associated with the development of cardiomyopathy. The genetic variant DCM1 is inherited in an autosomal dominant mode with incomplete penetrance.

The second genetic variant found in DCM2 is the g.22321955C>T mutation in the TTN gene. The mutation leads to a change of the amino acid glycine to arginine. The TTN gene encodes the protein titin, which is an essential component of sarcomeres. Post-translational modifications of titin can lead to profound changes in cardiomyocyte function. The TTN gene is involved in the proper functioning of cardiac contractions. The DCM2 genetic variant is inherited in an autosomal dominant mode with incomplete penetrance.

In 2023, Niskanen et al. discovered two more genetic variants in the European Doberman population - DCM3 and DCM4. Both were detected on chromosome 5: chr5:53,109,178 (DCM3) and chr5:60,531,090 (DCM4). The dogs are affected by systolic dysfunction and left ventricular dilatation. The DCM3 genetic variant is inherited in an autosomal dominant mode with incomplete penetrance and the DCM4 variant is inherited in an autosomal recessive mode with incomplete penetrance.

The combinations of the individual genotypes of the genetic variants DCM3 and DCM4, which are the most common in the European Doberman population, are shown in the table below, where the different risk categories can be clearly seen.

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Risk < 50% - genotypes N/N (DCM3) and N/N (DCM4); N/N (DCM3) and N/DCM4

Risk 50 – 75 % - genotypes N/DCM3 and N/N (DCM4); N/DCM3 and N/DCM4

Risk > 75 % - genotypes DCM3/DCM3 and N/N (DCM4); N/N (DCM3) and DCM4/DCM4; DCM3/DCM3 and N/DCM4; N/DCM3 and DCM4/DCM4;

The highest risk carry the genotypes DCM3/DCM3 and DCM4/DCM4.

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The inheritance of dilated cardiomyopathy DCM1, DCM2, DCM3 and DCM4 in Dobermans is characterized by incomplete penetrance. Individuals who test as genetically affected may develop severe symptoms, but this is not the rule. Some individuals are mildly affected, while others are not affected at all. The genetic test will help identify individuals who are at risk of manifesting the disease. However, it does not help us to detect to what extent, if any, the individual will experience symptoms during its lifetime.

Resulting genotypes when all known genetic variants are included:

• N/N; N/DCM4 - the individual carries none of the previously known genetic variants or carries one copy of the DCM4 genetic variant, is healthy
• N/DCM1; N/DCM2; N/DCM3 - the individual carries one copy of the risk genetic variant, risk of developing dilated cardiomyopathy
• DCM1/DCM1; DCM2/DCM2; DCM3/DCM3; DCM4/DCM4 - individual carries two copies of the risk genetic variant, risk of developing dilated cardiomyopathy

If an individual carries a combination of multiple risk genotypes, the likelihood of developing DCM increases.

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Reference:

Meurs, K.M., Fox, P.R., Norgard, M.M., Spier, A.W., Lamb, A., Koplitz, S.L., & Baunwart, R.D. (2007). A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman pinscher. Journal of Veterinary Internal Medicine, 21(5), 1016-1020. doi: 10.1111/j.1939-1676.2007.tb03058.x

Owczarek-Lipska, M., Mausberg, T., Stephenson, H., Dukes-McEwan, J., Wess, G., & Leeb, T. (2013). A 16-bp deletion in the canine PDK4 gene is not associated with dilated cardiomyopathy in a European cohort of Doberman Pinschers. Animal Genetics, 44(2), 239-239. doi: 10.1111/j.1365-2052.2012.02396.x

Meurs, K.M., Lahmers, S., Keene, B.W., White, S.N., Oyama, M.A., Mauceli, E., & Linblad-Toh, K. (2012). 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. Human Genetics, 131(8), 1319-1325. doi: 10.1007/s00439-012-1158-2

Tharp CA, Haywood ME, Sbaizero O, Taylor MRG, Mestroni L. The Giant Protein Titin's Role in Cardiomyopathy: Genetic, Transcriptional, and Post-translational Modifications of TTN and Their Contribution to Cardiac Disease. Front Physiol. 2019 Nov 28;10:1436. doi: 10.3389/fphys.2019.01436. PMID: 31849696; PMCID: PMC6892752.

Niskanen, Julia E., et al. "Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human." Genome medicine 15.1 (2023): 73.

Wess, G., et al. "Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups." Journal of Veterinary Internal Medicine 24.3 (2010): 533-538.

Simpson S, Edwards J, Emes RD, Cobb MA, Mongan NP, Rutland CS. A predictive model for canine dilated cardiomyopathy-a meta-analysis of Doberman Pinscher data. PeerJ. 2015 Mar 26;3:e842. doi: 10.7717/peerj.842. PMID: 25834770; PMCID: PMC4380154.