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Dilated cardiomyopathy

​Quick SummaryDilated cardiomyopathy is a condition in which the heart has a decreased ability to pump blood. Two mutations associated with dilated cardiomyopathy in Doberman Pinschers have been identified. Testing for these mutations can identify individuals at risk for developing clinical symptoms of disease.Phenotype: Dilated cardiomyopathy is a heart condition in which the muscles degenerate, causing the walls of the heart to become thin, resulting in reduced contractibility. This can lead to congestive heart failure.
Mode of Inheritance: Autosomal dominant with incomplete penetrance
Alleles: N = Normal, DCM1 = dilated cardiomyopathy 1 variant present, DCM2 = dilated cardiomyopathy 2 variant present
Breeds appropriate for testing: Doberman Pinscher
Explanation of Results:
  • Dogs with N/N genotype do not have either of the known DCM variants.
  • Dogs with N/DCM1 or N/DCM2 genotypes are at risk to develop cardiomyopathy. If two heterozygotes with the same mutation are mated, approximately 75% of the puppies are at risk of developing disease. Dogs heterozygous for both variants, N/DCM1 and N/DCM2, are at greater risk to develop clinical symptoms relative to those with only one variant.
  • Dogs with DCM1/DCM1 or DCM2/DCM2 genotypes are at risk to develop cardiomyopathy. All puppies produced from matings of dogs with either of these homozygous genotypes are at risk for developing dilated cardiomyopathy.
​Additional DetailsDilated 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: 
The abstract of Kate Meurs’ paper which was peer  reviewed and published in The Journal of Veterinary Internal Medicine in May  2010, in layman’s terms.

Or you can see this presentation and have your Dobermann tested if you follow this link:  http://www.vetmed.wsu.edu/pets/videos/Doberman/index.aspx

Dilated cardiomyopathy (DCM) is a familial disease in  the Doberman pinscher that often causes sudden death or heart failure. We have  previously shown Doberman pinscher DCM to be inherited as an autosomal dominant  trait. In humans, several causative genes for familial dilated cardiomyopathy  have been identified including cystoskeletal, sarcomeric and mitochondrial  genes. We and others have excluded many of these genes as candidates for DCM in  this breed. We hypothesized that a genome-wide SNP genotyping array might  identify a genetic alteration associated with familial DOBE DCM. 
          
     DNA samples from adult Dobermans with  DCM (LVDD > 4.8 cm and Fractional shortening < 20%) and apparently  unaffected Dobermans over 10 years of age were evaluated with a genome-wide SNP  genotyping array.  We identified an area of statistical significance on  canine chromosome 14. Through additional evaluation we identified a deletion  mutation in a gene that encodes for a mitochondrial protein that contributes to  cardiac regulation of glucose metabolism. The deletion strongly correlated to  the development of this disease in this breed (p = <0.0001). It should be  remembered that in human beings there are more than 20 different genetic  mutations in different genes that cause this disease. It is unlikely that this  is the only cause of DCM in this
breed.

               In human beings, genetic dilated  cardiomyopathy is a disease of variable penetrance. This means that not all  people with the mutation will develop the disease, or to the same disease  severity. In other words, not everyone with a genetic mutation will have the  disease penetrate it to the same extent. It is very likely the same in the  dog-- not every dog with the mutation will show the disease. Finally, since  there is likely to be a high prevalence of this mutation in the Doberman and  the penetrance is variable, we
do not recommend removing all dogs with the  disease.

At this time, these are our recommendations:

            Dilated Cardiomyopathy Mutation (DCM) is a form of heart  disease in the Doberman Pinscher dog. It is inherited and our laboratory has  identified a mutation responsible for the gene in some Doberman Pinschers.  However, it should be noted that in human beings with the same disease, there  are many different genetic mutations which can cause this disease. We do not  yet know if this is the only mutation in the Doberman Pinscher or if there will  be many different mutations. Please keep in mind that we are continually  learning about this disease and recommendations will be altered as we obtain  more information. 

Currently our interpretation of the test is:

Negative results: 

The absence of the mutation in this dog, DOES NOT mean that it will never develop the disease. It means that it does not have the  only known mutation that can cause the disease in the dog at this time.


Positive Results:

Dogs that are positive for the test will not necessarily  develop significant heart disease and die from the disease. Some dogs will  develop a very mild form of the disease and will live quite comfortably, some  may need treatment.  Importantly, breeding decisions should be made  carefully. At this time we do not yet know what percentage of Doberman  Pinschers will be positive for the mutation. However, removal of a significant  number of dogs from the breeding population could be very bad for the Doberman 
Pinscher breed. Remember that dogs that carry this mutation also carry other  important good genes that we do not want to lose from the breed.

Positive Heterozygous (1 copy of the mutated gene and  1 copy of a normal gene)

Dogs that are positive heterozygous should
be carefully  evaluated for signs of disease (Holter monitor and an
echocardiogram). If  abnormalities are detected, possible treatment options
should be discussed with  your veterinarian. Adult dogs that do not show signs
of disease and that have  other positive attributes could be bred to mutation
negative dogs. Puppies may  be screened for the mutation and over a few
generations, mutation negative  puppies may be selected to replace the mutation
positive parent and gradually  decrease the number of mutation positive dogs in
the population.

Positive Homozygous (2 copies of the mutated gene)

We recommend not breeding the homozygous dogs. Dogs that  are homozygous for the mutation appear to have more significant disease and  will certainly pass on the mutation.
              I hope that helps- I will keep you updated as to the  date of the webinar so you may distribute that.
Thank you for your interest! 

All the best
Kate Meurs

Fireax Dobermanns