Dilated cardiomyopathy is an inherited, potentially fatal heart disorder. In affected dogs, the left ventricle is often dilated, resulting in a progressive thinning of the wall and irregular heartbeat, thus decreasing overall cardiac function and output. This lack of adequate circulation can lead to fluid accumulation in the lungs as well as other parts of the body. Affected dogs can show progressive deterioration leading to death or can be relatively asymptomatic and then die suddenly.
In humans, over 60 different genes have been identified that result in inherited cardiomyopathy. Dr. Kate Meurs and colleagues at North Carolina State identified mutations in two independent genes that have been associated with dilated cardiomyopathy. Specifically, a deletion of 16 DNA bases in pyruvate dehydrogenase kinase 4 (PDK4 g.20,829,667_20,829,682del), known as DCM1, results in a gene product suspected to cause cardiac issues. The DCM1 variant is predicted to alter the mitochondrial PDK4 protein assembly pattern because it eliminates a splice site. Since mitochondria are one the major sites of energy generation within a cell, the resulting negative impact of reduced energy generation within cardiac tissue is hypothesized to result in cardiomyopathy.
The second associated variant is a missense mutation in titin gene (TTN, g.22321955C>T, p. 8898G>R) known as DCM2. The DCM2 variant, which changes an amino acid conserved across mammals, is predicted to alter one of the gene products (protein) immunoglobulin -like (Ig) domains. The Ig domains function like springs within a muscle fiber, and the variant is predicted to reduce the elastic nature of the protein, negatively impacting cardiac function.
For DCM1 the risk of developing cardiac disease is 7 fold for animals with one or two copies of this variant. The relative risk for DCM2 has not been determined. Dogs with both DCM1 and DCM2 have been reported to be at the highest risk for developing disease.
A single affected copy of either gene is necessary to develop symptoms, but not all dogs with DCM1, DCM2, or both mutations will develop disease. Since a single copy of either mutation can increase risk for disease, this trait is considered a dominant trait. However, since not all dogs with these mutations go on to develop disease, these mutations are thought to be incompletely penetrant. Other factors likely explain the incompletely penetrant nature of this disease, and studies to investigate additional genetic and non-genetic risk factors are ongoing. Recently it was noted that in a European Doberman Pinschers sample set, the DCM1 mutation was not as correlated with disease risk as it is in the original Doberman study cohort.
Further, not all Doberman Pinschers with dilated cardiomyopathy have either of these mutations. Therefore, it is also likely that additional as of yet unidentified variants in these or other genes are involved in disease presentation and progression. Continued research is needed to identify additional genetic and non-genetic risk factors.
However, these DNA tests can help owners and clinicians identify at-risk dogs for careful clinical evaluation. Further, breeders can use the results of this test in assisting with mate selection.
Note: These tests are specific for the autosomal dominant mutations present in the Doberman Pinscher. Other as of yet unidentified variants that cause dilated cardiomyopathy are thought to be present in this breed.