In the first part of this examination of risk assessment and genetic testing, I dissected the concept of risk. Although relative risk is incomplete without the perspective provided by absolute risk, logistical constraints within veterinary research often limit this perspective. There is still value to these tests. In this next entry, I want to look at specific genetic tests where the result is functionally a risk assessment. Hopefully, you will better understand how to use the information provided by these tests with the goal of producing better dogs with each generation.
Genetic testing for dermatomyositis (DMS) is a true risk assessment test. Results from this test place a dog in risk categories of low, medium, high, and unknown. This type of risk assessment is uncomplicated. For each possible genotype listed in the report, the percentage of affected dogs in that group has been determined. Based on the genotype, the likelihood of an individual dog developing DMS is classified as low (0% - 5%), moderate (33% – 50%), or high (90% – 100%). These percentages correlate with the absolute risk for these dogs. With this test result, decisions about breeding a dog can be made. Even dogs that come back as high risk can still be maintained within a breeding program with the appropriate mate limiting the risk for the next generation. For more information on DMS and how it is reported see Testing for Dermatomyositis Risk.
Another genetic test that gives an associated risk is the test for Chondrodystrophy (CDDY). CDDY has a reported relative risk for intervertebral disc disease (IVDD) requiring surgical correction of 5 – 15%. Meaning in one study, 5 to 15 dogs out every 100 that had the 12-FGF4 mutation required surgery to correct. How bad is that? First, Dachshunds and French Bulldogs were not included in the evaluation because of the high frequency of the mutation in these breeds. Next, only dogs that required surgery to correct the presentation of IVDD were used to determine this relative risk. Dogs diagnosed with IVDD but treated non-surgically were not included. These two parameters would suggest the risk for IVDD because of the 12-FGF4 mutation is theoretically higher. It does raise an interesting point about risk. By leaving out dogs that were treated non-surgically, it focuses the risk assessment on one the most relevant aspects of IVDD: The cost of surgery to treat this disease. This is often prohibitive and may increase the resulting mortality of the condition. IVDD presents along a spectrum of severity. Some dogs require minimal treatment and recover without further issue. Other dogs experience significant discomfort and do not respond to conservative treatment modalities. By only including the dogs that require the more intensive treatment of surgery, the researchers have focused the relative risk on what matters to most dog owners. This is like the risk of developing a disease versus the risk of dying from a disease. One is much more significant than the other.
What is the relative risk for a Labrador having the ATP7B mutation developing complications due to copper toxicosis? Unfortunately, sample size and logistics have precluded any significant statistical analysis for dogs having this mutation and concurrently presenting with the disease. Copper toxicosis tends to present later in a dog’s life creating a challenge for compiling statistics as these dogs become lost to researchers over time. Many Labradors having this mutation never develop clinical signs of copper poisoning. One explanation is in the effect the mutation has on an affected dog. The ATP7B mutation limits the dog’s ability to excrete excess copper from its body. What causes clinical signs is toxic levels of copper in a dog’s system. Should a dog retain copper, as a result of the mutation, but never acquire a toxic level, then clinical signs may not present. Regular monitoring dogs with this mutation through a veterinarian would be prudent and expand preventative or treatment options. Along with the disease associated ATP7B mutation, there is the risk limiting ATP7A mutation. This mutation reduces the amount of copper the dog can absorb from the diet. Less copper going in the dog reduces the chance of excessive copper building up in the system. What ultimately determines if a dog develops clinical signs is the level of copper. Therefore, minimizing copper in the dog’s diet and environment may prevent the disease. The genetic test can be the early warning a dog owner needs to engage in preventative care under the direction of their veterinarian.
Some genetic tests for disease causing mutations are controversial because they are, in effect, risk assessments for many breeds. These are diseases where a test for the causal mutation is available but there is incomplete penetrance of the disease. Incomplete penetrance means not every dog that should be affected by the mutation presents clinically with the disease. It demonstrates that we do not understand what modifies or prohibits the expression of the mutation and why that variability exists. An example of a disease with incomplete penetrance is degenerative myelopathy (DM). DM is an ancient recessive mutation found within many breeds. Some breeds have a clinical history of developing DM. The German Shepherd and the Bernese Mountain Dog are examples of breeds that are strongly associated with this disease and testing for the disease-causing mutation can help progress the breeds away from the disease. However, many breeds that regularly test positive for two copies of the DM mutation never develop the clinical condition. For these breeds the genetic test is a risk assessment with a significant amount of unknown information concerning the absolute risk. Results from these tests should be interpreted carefully so dogs are not removed unnecessarily from a breeding population.
Every pure-bred dog comes from a limited gene pool. As dogs are removed from breeding, that gene pool is further reduced. One value of genetic testing is it offers guidance to the breeder about when this is necessary and when it is possible to preserve a dog within a breeding program. For tests that are risk assessments, the result is one piece of the puzzle, not the whole picture. Breeders should operate with a set of priorities for their program. Each breeding pair should further the breeder’s objectives. By focusing on the how each dog fits within the priority framework established by the breeder, a risk-based genetic test result can be weighted appropriately in the decision to breed that dog or not.
Interpreting genetic test results can be complicated. This is simplified when the test is for a disease-causing mutation. When the test is functionally a risk assessment, interpretation may be confusing. Understanding how the concept of risk applies to genetic testing and having an increased knowledge of the specific tests that produce risk assessments give the breeder greater value from these tests. Testing for DMS is a simple example of a functional risk assessment, while tests for CDDY and Copper Toxicosis can be more problematic. Having some knowledge of the clinical frequency of a disease provides the perspective to understand tests for disease-causing mutations that have incomplete penetrance. At Paw Print Genetics we know this is not always easy to understand. That is why our veterinarians and geneticists are available for consult free of charge. They can help you interpret your results and increase your knowledge about the functionality of the tests so you can incorporate the information and improve your breeding program.
References:
Evans JM, Noorai RE, Tsai KL, Starr-Moss AN, Hill CM, Anderson KJ, Famula TR, Clark LA. Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci. PLOS Genetics. 2017 Feb 3; 12(2) [PubMed: 28158183]
Dickinson PJ, Bannasch DL. Current Understanding of the Genetics of Intervertebral Disc Degeneration. Front Vet Sci. 2020 Jul 24;7:431. doi: 10.3389/fvets.2020.00431. eCollection 2020. [PubMed: 32793650]
Batcher K, Dickinson P, Giuffrida M, Sturges B, Vernau K, Knipe M, Rasouliha SH, Drögemüller C, Leeb T, Maciejczyk K, Jenkins CA, Mellersh C, Bannasch D. Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs. Genes. 2019; 10(6):435. https://doi.org/10.3390/genes10060435
Fieten H, Gill Yadvinder, Martin AJ, Concilli M, Dirksen K, van Steenbeek FG, Spee B, van den Ingh TSGAM, Martens ECCP, Festa P, Chesi G, van de Sluis B, Houwen RHJH, Watson AL, Aulchenko YS, Hodgkinson VL, Zhu S, Petris MJ, Polishchuk RS, Leegwater PAJ, Rothuizen J. The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. Dis Model Mech. 2016 Jan;9(1):25-38. doi: 10.1242/dmm.020263. [PubMed: 26747866]
Woloshin S, Schwartz LM, Welch HG. Know Your Chances: Understanding Health Statistics. Berkeley (CA): University of California Press; 2008. Chapter 2, Putting Risk in Perspective. Available from: https://www.ncbi.nlm.nih.gov/books/NBK126167/