Interpreting Doberman Pinscher Type Genetic Risk Factors for Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a type of heart disease that affects the heart muscle, causing it to become weakened. This weakening of the heart muscle impairs its ability to pump blood efficiently, leading to dilation of the heart chambers. Clinical signs include fatigue, shortness of breath, an increased risk of abnormal heart rhythms, and heart failure. DCM can have multiple causes, including inherited and nutritional.

An echocardiogram is necessary for diagnosis, which can be performed by board-certified veterinary cardiologists. Even with a normal echocardiogram at a point in a dog’s life, the dog can still go on to develop DCM in the future. Holter monitors worn for 24 hours, which record ECGs, are also used to diagnose arrhythmias due to DCM.

Doberman Pinschers are predisposed to a more severe form of DCM with an onset between 4 and 10 years. Although this disease is strongly thought to be genetic, the cause is still unknown. To help decrease the risk of breeding dogs with this DCM, the Doberman Pinscher Club of America currently recommends echocardiograms and Holter monitors on breeding stock. Unfortunately, these tests are not perfect at determining future disease. They are a snapshot in time and assess the dog at that specific point in their lives. A dog may have normal test results at the time of breeding, but still develop DCM in the future.

Genetic tests show promise at predicting which dogs will develop disease before they are bred. The AKC Canine Health Foundation has funded multiple researchers to help identify these genetic variants, which has led to further studies evaluating their significance. As a result of these discoveries, AKC CHF-funded gene therapy studies are also underway and show promise for helping dogs affected with DCM.

Although some genetic variants have been identified that can indicate an increased risk for developing DCM in the future, they are not perfect.  These tests can be challenging for breeders to interpret. False positive or false negative results can have impacts on the breed’s genetic diversity. In fact, these genetic variants are not included in the Doberman Pinscher Club of America’s recommendations for the breed, whereas the phenotype tests of echocardiogram and Holter monitors are recommended.

AKC DNA + Health includes two genetic variants that are associated with an increased risk of DCM for Doberman Pinschers:

• Dilated Cardiomyopathy (Doberman Pinscher Type Risk Factor, Variant 1)
  • This specific genetic variant investigates a deletion in the PDK4 gene and is associated with disease in Doberman Pinschers. This genetic variant is inherited in an autosomal dominant manner with incomplete penetrance. In other words, not every dog with this genetic variant goes on to develop the disease DCM.
• Dilated Cardiomyopathy (Doberman Pinscher Type Risk Factor, Variant 2)
  • This specific genetic variant investigates a single nucleotide polymorphism (SNP) in the TTN gene and is associated with disease in Doberman Pinschers.

A follow up study evaluating both of these variants in 48 Doberman Pinschers with DCM showed that 28 (58%) had the TTN variant 2 alone, 10 dogs (21%) had both variant 1 and 2, 6 dogs (12.5%) had neither variant, and only 4 dogs (8.3%) had just the PDK4 variant 1 alone.⁴ This study suggests that factors other than these known variants can lead to DCM in Doberman Pinschers. In other words, a dog without either of these variants detected can develop DCM.

Furthermore, the above study evaluated only dogs with DCM. These variants can also appear in dogs that do NOT go on to develop DCM.^1,2 One study found no association of the PDK4 variant in a European cohort of Doberman Pinschers.²

Are these genetic variants associated with DCM in other breeds?

Sometimes dogs from other breeds also test positive for these Doberman Pinscher DCM genetic variants. However, the interpretation of these results in other breeds is unknown. The studies for these genetic variants were performed in Doberman Pinschers, and as of the writing of this article, their significance in other breeds has not been evaluated. If a breeder has a dog that tests positive for these genetic variants and is concerned, then yearly screening with a cardiologist will help evaluate the dog for the clinical disease of DCM. Caution should be made in using these genetic variants to make breeding decisions. Instead, the echocardiogram and/or Holter monitor results are more important in weighing breeding decisions.

Concluding Comments

Although genetic variants for DCM in Doberman Pinschers show promise of predicting disease, their incomplete penetrant mode of inheritance makes their interpretation challenging. Phenotype tests of echocardiograms and Holter monitoring remain the gold standard for diagnosing this disease. Regular screening is recommended for all at-risk breeds, regardless of their test results for the DCM genetic variants. If a breeder is concerned that their male dog may develop DCM, he/she can consider freezing semen at a young age and waiting to see if that dog develops DCM later in life. The breeder can then go back to that semen once more information about the dog’s heart can be gathered. Unfortunately, the option to delay breeding is not widely available in females. Lastly, these genetic variants were identified in Doberman Pinschers and have not been validated in other breeds. Breeding decisions based on these test results should be made with caution. Instead, consider making health and breeding decisions in other breeds based on echocardiogram and Holter monitor results rather than the results of these genetic variants.

1. 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 Aug; 131(8):1319-25.
2. 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 Apr;44(2):239.
3. Meurs KM, Friedenberg SG, Kolb J, Saripalli C, Tonino P, Woodruff K, Olby NJ, Keene BW, Adin DB, Yost OL, DeFrancesco TC, Lahmers S, Tou S, Shelton GD, Granzier HG. A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death. Hum Genet. 2019 May;138(5):515-524.
4. Meurs KM, Stern JA, Adin D, Keene BW, De Francesco TC, Tou SP. Assessment of PDK4 and TTN gene variants in 48 Doberman Pinschers with dilated cardiomyopathy. J Am Vet Med Assoc. 2020 Nov 15;257(10):1041-1044.