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DCM in Dobermans

Overview

Wisdom Panel™ is excited to announce the launch of a ground-breaking panel of tests for Dobermann Pinscher breeders to screen for Dilated Cardiomyopathy (DCM) risk. These tests are now included in the Optimal Selection product (they are not available separately).

As part of a collaboration between research groups spanning several countries – including universities at Helsinki, Bern, Ljubljana, Munich, Uppsala, and Utrecht – Wisdom took part in the largest study of Dobermann DCM to date, uncovering new genetic risk factors. This offering represents the first opportunity for Dobermann breeders to use these discoveries in their breeding programs. This is a resource page that we'll keep up to date with the most current information! 

February 9th, we will be hosting a live webinar which will feature a panel discussion with key researchers and clinical experts as they break down these discoveries and talk about practical ways Doberman breeders can apply them in their breeding programs.

Register here for the February 9th webinar, at 10am EST

If you would like to view the European webinar held in November 2023, it can be viewed here.

What is Dobermann Dilated Cardiomyopathy (DCM)?

DCM is a severe condition in which the walls of the heart become thin and weak, leading to heart enlargement and eventual heart failure due to a decreased ability to pump blood. It is the second most common heart disease in dogs  and prevalence of dilated cardiomyopathy (DCM) in the Dobermann breed is estimated at 58%. The condition typically presents in middle to older aged dogs, often past the time of breeding, which makes the ability to genetically screen for risk of this condition crucial for the health of future generations. 

DCM is a complex disorder that is influenced by hereditary and non-hereditary factors, and signs of the disease vary between individuals. Affected dogs may show exercise intolerance, persistent coughing, weakness, weight loss, breathing difficulties, fainting, or swelling of the abdomen due to fluid build up (known as ascites). Although males and females have equal rates of DCM, male Dobermanns are more likely to show earlier clinical signs and congestive heart failure than females. Some may only experience heart arrhythmias (irregular heartbeats) which can cause sudden death in up to 30% of Dobermanns without any other signs. 

Though our understanding of DCM and treatment options continues to progress, dilated cardiomyopathy remains a serious disorder. Because it is an incurable and progressive condition, the focus of treatment is on managing disorder progression and optimising quality of life. 

While there is no cure, dogs who develop DCM can receive therapy to control arrhythmias, improve the heart’s function and manage congestive heart failure. In addition, working with a veterinarian on appropriate diet and exercise plans can help improve quality of life. And, because stress can worsen clinical signs, keeping dogs as calm and stress-free as possible can be beneficial.

The Dobermann Study: DCM3 & DCM4

Published just in September of this year (2023), the Dobermann DCM study represents the culmination of 20 years of scientific research on Dobermanns. Over 540 clinically characterised privately owned Dobermanns were included in the study. Genome-wide SNP array genotyping was performed on 431 dogs, and whole-genome sequencing on a separate set of 13 dogs, identifying a statistically significant association between DCM and two regions on canine chromosome 5. Importantly, this finding replicates a previous study of DCM in Dobermanns in Germany and the UK, adding credibility and confidence to the chromosome 5 association. 

Two highly significant variants (SNP markers) emerged from these analyses, both on chromosome 5: chr5:53,109,178 (DCM3) and chr5:60,531,090 (DCM4). Although these markers are located relatively close together on chromosome 5, they appear to contribute to disease risk independently, although the number (and combination) of risk variants influence the overall risk level. No association was found for DCM risk between DCM1 (PDK4) and DCM2 (TTN) variants in this European study set, in line with a previous European study.

DCM3 is associated with less overall risk, but follows a dominant inheritance pattern, with increased risk associated with one or two copies of the risk variant. DCM4 is associated with greater risk of DCM development, but follows a recessive inheritance pattern, in which increased risk is associated only with dogs carrying two copies of the risk variant in the absence of DCM3. 

Please note that the causal risk variants were not identified in the study and that DCM3 and DCM4 are highly associated linkage markers.

Read more about the study and its findings here.

Using DCM3 and DCM4 test results

Risk Definitions:

Based on the rate of development of DCM in the study dogs, we have developed the following risk categories for ease of interpretation. Please note that even dogs that carry no copies of the DCM3 and DCM4 variants are still at risk for DCM due to the complex and multifactorial nature of the disease, but at much lower risk than other categories. 

Low risk: 0-50% likely to develop DCM in their lifetime

Medium risk: 51-75% likely to develop DCM in their lifetime

High risk: 76-99% likely to develop DCM in their lifetime

Highest risk: 100% likely to develop DCM in their lifetime

 Breakdown of the Dobermann Population by Genotype:

Percentages do not add up to 100% due to rounding

 

What to do in the breed as a whole?

Due to the limited number of dogs with zero copies of either DCM3 or DCM4 variants, and the complex nature of DCM, breeders should seek to slowly reduce the frequency of highest-risk dogs over many generations. By doing this, the good features and genetics of the highest risk dogs can be safely passed on to future litters while incrementally decreasing the risk of development of DCM in the near term. The goal of eliminating all risk factor carriers from the population is tempting in light of the severity of the disease, but this risks the overuse of some sires, formation of population bottlenecks and loss of genetic diversity in the breed. Each breeding decision will therefore need to be customised and, ideally, made in light of the health of the whole breed. 

What to do in individual breeding programs?

A dog should not be excluded from breeding on the basis of a risk panel but on a holistic evaluation of their merit to the breed. Carriers, including high and highest risk dogs, should be matched with complementary dogs in order to bring about slow, positive progress toward all low risk litters without losing bloodlines. DCM4 has a stronger influence on risk and a recessive inheritance. It is therefore recommended that breeders first focus on lowering DCM4 frequency in the breed, while balancing other DCM risk factors.

The table below shows some example matings, aiming to lower the risk in the offspring where possible, even when one of the parents is a high or medium risk individual.

Parent 1

(genotype  DCM3/DCM4)

Parent 2

(genotype DCM3/DCM4)

Possible genotypes of puppies (percentages are what would be expected on average)

AA/GG

0/0 copies

AA/GG

0/0 copies

100% low risk (AA/GG or 0/0 copies)

AA/GG

0/0 copies

AA/AG

0/1 copies

100% low risk (50% AA/AG or 0/1 copies, 50% AA/GG or 0/0 copies)

AA/GG

0/0 copies

AA/AA

0/2 copies

100% low risk (AA/AG or 0/1 copies)

AA/GG

0/0 copies

AG/GG

1/0 copies

50% low risk (AA/GG or 0/0 copies), 50% medium risk (AG/GG or 1/0 copies)

AA/GG

0/0 copies

GG/GG

2/0 copies

100% medium risk (AG/GG or 1/0 copies)

AA/GG

0/0 copies

AG/AG

1/1 copies

25% low risk (AA/GG or 0/0), 25% medium risk (AG/GG or 1/0 copies), 25% low risk (AA/AG or 0/1 copies), 25% medium risk (AG/AG or 1/1 copies)

AG/GG

1/0 copies

AA/AG

0/1 copies

25% low risk (AA/GG or 0/0 copies), 25% medium risk (AG/GG or 1/0 copies), 25% low risk (AA/AG or 0/1 copies), 25% medium risk (AG/AG or 1/1 copies)

GG/GG

2/0 copies

AA/AG

0/1 copies

50% medium risk (AG/GG or 1/0 copies), 50% medium risk (AG/AG or 1/1 copies)

GG/AA

2/2 copies

AA/GG

0/0 copies

100% medium risk (AG/AG or 1/1 copies)

GG/GG

2/0 copies

AG/GG

1/0 copies

50% medium risk (AG/GG or 1/0 copies), 50% high risk (GG/GG or 2/0 copies)

 

About DCM1 and DCM2 Testing:

The DCM1 and DCM2 discoveries were made in a US population of Dobermanns. However, additional studies suggest DCM1 (https://doi.org/10.1111/j.1365-2052.2012.02396.x) and DCM2 (https://doi.org/10.1186/s13073-023-01221-3) are not predictive of DCM risk in European Dobermanns. The findings of the original DCM1 and DCM2 studies in US Dobermanns have not been replicated to date.

In contrast, DCM3 and DCM4 were identified using Dobermanns from Germany and Finland, and further validated using Dobermanns from the Netherlands, Slovenia and Sweden. This replicated a previous study using Dobermanns from Germany, which was validated with Dobermanns from the UK. However, further research is needed to understand the clinical relevance of these risk variants in American and other Dobermann populations.

We recommend that DCM1 and DCM2 should be considered first, DCM3 and DCM4 second in US Dobermanns, and DCM3 and DCM4 primarily considered in European Dobermanns, until additional information about risk is understood within different subpopulations of the breed. Where possible it is advisable to breed away from risk variants by using a measured strategy to maintain diversity within the breed. This advice should not discourage using imported lines to maintain diversity.

For US Dobermanns:

The DCM1 and DCM2 variants are both considered autosomal dominant, meaning only one copy of either of those variants needs to be present for a Dobermann to be at increased risk of DCM, and they are not associated with the sex chromosomes. Not all dogs with the risk variant(s) will go on to develop DCM, so the variants are of incomplete penetrance. However, even if a carrier dog does not express DCM themselves, they can pass the risk variant(s) to their puppies. 

As with DCM3 and DCM4, the risk for developing DCM varies based on the combination of inherited variants. Dogs with one copy of a single variant (DCM1 or DCM2) are considered at higher risk than those clear of either risk variant, and dogs who inherit both risk variants are considered at highest risk of developing DCM. 

As with DCM3 and DCM4, it is recommended to select mating pairs based on complementary genotypes so that high-risk genotypes are avoided in the offspring. Dogs carrying one copy of a single variant (DCM1 or DCM2), or dogs with two copies of a single variant shouldn’t be excluded from breeding and, ideally, paired with a dog clear of either variant. To ensure that the fewest possible puppies are in the highest risk category, it is important to avoid outcomes when possible in which dogs could inherit both DCM1 and DCM2 risk factors. Subsequent generations should be tested before choosing breeding pairs to responsibly manage the condition in the breed and gradually work towards decreasing its incidence.

DCM1 and DCM2 Risk Definitions:

  • 37% of Dobermanns with one or two copies of the DCM1 risk variant will develop DCM
  • 50% of Dobermanns with one or two copies of the DCM2 risk variant will develop DCM
  • 60% of Dobermanns with one or two copies of the DCM1 variant and one or two copies of the DCM2 variant will develop DCM

(reprinted here based on the categories provided by the researchers who first identified the DCM1 and DCM2 variants)

Please be mindful that as research into risk factors for developing Dobermann DCM continues, our understanding of these risk variants may also change.

How to read DCM results in Optimal Selection reports:

DCM_example_report_1copyOS.pdf

Detailed disorder results findings can be viewed under Health in your digital web report. For easy reference and record-keeping, many breeders prefer to download a technical report of their tested dogs’ results. The technical report download feature can be found at the bottom of the Highlights page. 

Want to learn more?

Two free webinars will be offered to accommodate both North/South American and European breeders:

  • American breeders: February 9th 10am EST Register here.
  • European breeders: recording viewable here

    Webinars will be chaired by a panel of experts, including researchers involved in the DCM3/DCM4 study. Wisdom’s RSVP is requested in advance. Question suggestions for discussion at the webinar can be submitted below:

    Submit questions or topics for discussion in the webinar here

    American webinar panelists:

    • Hannes Lohi, PhD, Professor of Veterinary Genetics at the University of Helsinki and leader of the team that discovered the novel DCM genetic risk factors
    • Josh Stern, DVM, PhD, DACVIM (Cardiology), associate dean of research at NCSU College of Veterinary Medicine, and founder of the Stern Translational Cardiac Genetics and Pharmacogenomics Laboratory at UC Davis.
    • Oliver Forman, PhD, Genetic Research Director at Wisdom Panel and UFAW Companion Animal Welfare Award winner.

     

     

     

     

    Next Steps: How You Can Help

    Wisdom Panel is planning a research study to validate the DCM3/DCM4 study findings in a North American group of Dobermanns, as well as to reevaluate the association of DCM1/DCM2 with DCM and the combined risk for all four risk markers. This will require DNA samples from Dobermanns with cardiac screening (echocardiograms and Holter monitoring) results. We are still in the early stages of planning this research study and will post more information here about how breeders can participate once the study design is finalised.

    Breed Clubs and Associations:

    We are always interested in partnering with breed clubs! If you represent a Dobermann club or association and wish to partner with us on research and education, and to receive discounted testing, please contact breeder@wisdompanel.com for more information.

    If you have a Dobermann over the age of 10 that is still alive and has not developed DCM, or have a dog with Longevity Certification (LC) or Bred for Longevity Certification (BFL), you may be eligible for complimentary testing! Please apply here.

    FAQ:

    How accurate is DCM3 and DCM4 testing?

    The markers used for our testing are the same as those used in the published study, and the frequency at which we found the variants was comparable to those found in Dobermanns in the study. All disorder tests we offer are evaluated for their reliable performance as part of a standardised quality assurance process, with an expected >99.99% accuracy. 

    Is DCM3/DCM4 testing significant for all Dobermanns, or just European ones?

    Although the study was not performed in Dobermanns of North American descent, it did involve Dobermanns from several European countries. The frequencies at which the variants were found were similar between North American and European Dobermanns, and the genes implicated are involved in healthy cardiac functioning, so we have evidence to believe these variants impact risk of DCM development in North American lines of Dobermanns as well. We are planning a study to confirm they are associated with DCM risk in North American Dobermanns in the future.

    Why does no one else offer DCM3 and DCM4 testing?

    Wisdom Panel participated in the original research study, so we were able to be the first to develop accurate testing to screen dogs as part of our contribution to that research.

    How do DCM3 and DCM4 compare to DCM1 and DCM2 in terms of risk for my dog?

    The short answer is that the most recent, highest-powered study to date found no association of DCM1 and DCM2 with risk of DCM development in European Dobermanns, but did find an association with risk factors on chromosome 5 (DCM3 and DCM4). Other studies have yielded  similar findings - no association of DCM1 and DCM2 with DCM, and risk associated with variants on chromosome 5 in European Dobermanns. No one has yet attempted to replicate the original studies of DCM1 and DCM2, or DCM3 and DCM4 in North American line Dobermanns, so total risk for that group remains unconfirmed.

    If my dog was found to be at high risk of developing DCM, should I talk to my veterinarian about starting medical treatment?

    If your dog is genetically considered high risk, please talk to your veterinarian about his/her recommended schedule for echocardiogram and Holter screening for your dog, and when or if you should begin treatments.

    Should I be using carriers in my breeding program?

    On average, only 9% of the Dobermann population is DCM3 and DCM4 negative, so use of carriers is not only recommended, it is necessary in the initial phases of genetic population management of DCM. With time, and a greater proportion of lower risk dogs, use of the highest risk dogs in breeding can be reduced, but this should take place over many generations. The initial goal should be reduction of highest risk in puppies.

    Should I be using high or highest risk DCM3/DCM4 dogs in my breeding program?

    41% of the Dobermann population falls into the high or highest risk categories, so use of these dogs in breeding is not only recommended, it is necessary in the initial phases of genetic population management of DCM. Attention should be given to mating dogs with complementary genotypes. Example pairing options are listed earlier on this page to limit the number of high risk puppies, and avoid the highest risk category. With time, and a greater proportion of lower risk dogs, use of the highest risk dogs in breeding can be reduced, but this should take place over many generations.

    What should I do if my dog comes back with a high risk for DCM based on DCM3/DCM4 testing?

    Evaluate your dog for their total merit to your breeding program as you would normally - their temperament, their conformation, their athleticism and talent, their genetic screening results, their other health screening results, their unique contributions to the genetics of your kennel and the breed, etc. If they are of excellent merit but high or highest risk for DCM development, keep in mind that 41% of the Dobermann population is in this category, and consider breeding them to a complementary dog that will produce lower risk puppies. It is ultimately up to you to make the final judgment, understanding that DCM risk will have to be managed for many generations.

    My dog was in the original study, but I did not receive results. Can I retest with you?

    Yes! We are happy to provide complimentary retesting for Dobermanns in the original study. Please provide proof of participation to breeder@wisdompanel.com and we would be happy to issue you a promotional code for a complimentary kit.

    I previously tested with MyDogDNA/Optimal Selection. Can I receive updated results?

    Please contact Customer Service at breeder@wisdompanel.com to inquire about retesting your Dobermann at reduced cost. Please provide your original sample ID in your email to expedite the process.

    My dog was tested for DCM1 and DCM2 previously, do I have to pay for the whole panel to receive DCM3 and DCM4 results?

    We understand that some of the tests included in Optimal Selection™ or MyDogDNA® may not be relevant to all individuals. But we can’t single out specific tests. One of the reasons our breeder testing is so comprehensive and affordable is because it is an automated panel test. In other words, it costs less to report on all variants using our custom chip than it would cost to run individual tests.

    What is my dog’s risk if they have low risk for DCM1 and DCM2 but high risk for DCM3 and DCM4 or vice versa?

    The relationship between DCM1/DCM2 and DCM3/DCM4 is clear for European Dobermanns - DCM3 and DCM4 risk are of established significance, and DCM1/DCM2 have been shown to have no association with risk. For North American Dobermanns, the relationship between risk and DCM1, DCM2, DCM3, and DCM4 results are less clear, but DCM3 and DCM4 are likely to be as significant to disease risk or more so than DCM1 and DCM2 based on the findings of the most recent study.

    Why is the DCM3/DCM4 research significant?

    It is the highest-powered study to date on the subject of Dobermann DCM, with 540 privately owned Dobermanns, and spans a 20 year period, between 1999 and 2019. The results refined the findings of a previous study on an associated risk marker on chromosome 5, along with the discovery of a second, more influential marker, also on chromosome 5. As with previous publications, it contested the significance of DCM1 (PDK4) and DCM2 (TTN) risk in European Dobermanns.

    Were there any nutritional or lifestyle impacts to age or incidence of DCM?

    The DCM3/DCM4 study did not examine lifestyle or nutrition as an exclusion or inclusion criteria for participation in the study. Recent publications from the FDA and others have discussed the possible impact of BEG (boutique, exotic, and grain-free) diets on incidence of DCM in many breeds. In particular, “eating pet foods containing peas, lentils, other legume seeds, or potatoes” as one of the first 10 ingredients were identified as risk factors. However, Dobermanns may have been underrepresented in the reported cases according to some nutritionists, in part because veterinarians assume a genetic cause of DCM in certain breeds prone to it. Taurine deficiency appeared to be the problem in a number of the reported cases, while others were suspected to have another, yet unknown, nutritional mechanism. Dobermanns with genetic DCM do not improve with taurine supplementation if they are not already deficient. 

    What about dogs with only heart arrhythmias / VPCs?

    Historically, a certain number of VPCs (ventricular premature contractions, a type of arrhythmia) within 24 hours was considered diagnostic for hidden or stage II DCM, but in light of the most recent study’s findings, additional research is needed. In the most recent study, dogs with just VPCs and a normal  echocardiogram were not explained by the  DCM3 and DCM4 risk factors. Unfortunately, the dogs in that group did not comprise an adequate sample size to discover associated risk markers.

    Are DCM3 and DCM4 markers linked or direct?

    While the DCM3 and DCM4 markers are highly significant, they are a signal of where in the DNA the causal defect is, rather than being the actual causal risk factors. The RNF207 and PRKAA2 genes, which have a possible role in cardiac muscle function, were confirmed to have abnormal RNA transcripts on RNA analysis of DCM affected dogs. However, the exact locations of the mutations causing the abnormal expression of RNF207 and PRKAA2 were not found. As the causal variants were not identified in this study, this test uses DCM3 and DCM4 as two strongly associated linkage markers, rather than the causative variants. 

    What is the significance of DCM1, DCM2, DCM3 and DCM4 variants in other breeds?

    All four currently offered variants have been found in other breeds. Their role in development of DCM or DCM risk in those breeds is not yet known. For this reason, at this time we are only reporting the 4 DCM variants in Dobermanns.

    How do I prioritise DCM risk testing with other recommended tests - hip dysplasia, vWD, eye conditions? 

    Hip dysplasia (HD), von Willebrand’s Disease, DCM screening (genetic and otherwise) and eye conditions, such as PHTVL/PHPV (persistent hyperplastic tunica vasculosa lentis/persistent hyperplastic primary vitreous) should all be considered as part of a holistic breeding management plan. Evaluate your dog for their total merit to your breeding program as you would normally - their temperament, their conformation, their athleticism and talent, their genetic screening results, their other health screening results, their unique contributions to the genetics of your kennel and the breed, etc. It may be helpful to consider the relative severity and commonness of the conditions you’re trying to balance, as well as the available treatments. For example, 41% of the Dobermann population is in the high or highest risk category, and 36% are in the medium risk category for DCM, which is a fatal disease. Comparatively, around 7% of Dobermanns are at high risk (carry two copies) for von Willebrands disease type I (vWD I), and 41% are at low risk (carry one copy) for vWD I, which is a clotting disorder that varies in severity from mild-severe bleeding tendencies, and risk can be reduced through appropriate planning. It is ultimately up to you to make the final judgment, understanding that DCM risk will have to be managed for many generations.

     

    Contact Us:

    For questions regarding previously tested Dobermanns, or status of current testing, please contact Customer Service at breeder@wisdompanel.com

    For questions regarding the study, please contact breeder@wisdompanel.com and include “North American Doberman DCM Study” in the subject line.

    Further Reading:

    Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

    Prevalence of Dilated Cardiomyopathy in Doberman Pinschers in Various Age Groups

    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

    A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death 

    A 16-bp deletion in the canine PDK4 gene is not associated with dilated cardiomyopathy in a European cohort of Doberman Pinschers 

    A Locus on Chromosome 5 Is Associated with Dilated Cardiomyopathy in Doberman Pinschers | PLOS ONE 

    Genetics of Human and Canine Dilated Cardiomyopathy 

    European Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in Doberman Pinschers 

    Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study) - PMC

    Diet-associated dilated cardiomyopathy in dogs: what do we know?