Just when you thought DNA testing was “simple” – my “Best of Health article for October 2021
IPFD Virtual Workshop 2021
2021 should have been the year for the 5th International Dog Health Workshop, organised by the International Partnership for Dogs. Unsurprisingly, it wasn’t possible to hold an in-person event that should have drawn participants from around the world.
However, on 28th September, IPFD ran a virtual workshop on the subject of standardising genetic testing. The aim of the workshop was to discuss and share relevant information around the challenges related to standardising genetic test reports. It was hoped that the workshop would identify outcomes and agree actions towards improving genetic reports, ultimately to the benefit of dog health and welfare.
The panel of experts included some names that will be well-known to many of my readers as I have referenced them in previous articles: Dr. Cathryn Mellersh (University of Cambridge), Dr. Jonas Donner (Wisdom Panel), Adam Boyko (Embark), Dr. Joanna Ilska (The Kennel Club), Dr. Danika Bannasch, (University of California, Davis), and Aimée Llewellyn-Zaidi (IPFD). Dr Brenda Bonnett, CEO of IPFD, welcomed everyone to the workshop. The participants included people from 12 different time-zones around the world so this was a middle of the night session for some people!
The pre-work for attendees included a series of video presentations by the panel and these covered 4 topics: Clarity of the test being performed; Risk/susceptibility tests vs. causal/direct mutation tests; Nomenclature and Genetic test application and advice to breeders.
Clarity of the test
From a test user’s (breeder/owner) perspective it’s important to understand that there are different types of DNA test and the implications of this for making breeding decisions. Cathryn Mellersh’s presentation helpfully set out some of the terms that test users need to know: Variant – is a DNA sequence which differs between individual dogs. This is sometimes called a marker. There are 3 types of variant; causal, associated and linked. A causal variant (or mutation) is one where it can be shown with robust evidence that it directly results in a disease. This evidence is usually assessed by peer-review in published research and, typically, applies to simple (Mendelian) diseases. These DNA tests are diagnostic.
An associated variant is one that is found in clinically affected dogs more often than in healthy dogs than you would expect by chance. However, it doesn’t mean that the variant is the cause of the disease and a DNA test would be predictive, rather than diagnostic. In complex diseases, it is likely that multiple associated variants will be involved; hence a DNA test for a single variant is unlikely to be very helpful to breeders in these cases.
Linked variants are ones which are located near to a causal variant on the same chromosome and can be used as proxies for causal variants. They form the basis of linkage DNA tests and are diagnostic for most dogs. However, test users need to be aware that there is always a risk of inaccurate results from linkage tests. There is also a debate about whether linkage test results should be recorded by Kennel Clubs because of the risk of errors.
Discussion in the workshop agreed that DNA labs need to make it clear which type of variant each of their tests is identifying so that users will know what type of result they are likely to get. This also raises the question of how risk-based results should be reported to breeders as well as a whole debate about validation of these tests and whether there is a risk threshold below which they should not be offered commercially.
The discussion of nomenclature used in DNA testing ranged from the naming of genes and variants through to naming of tests and the way results are reported. Cathryn Mellersh shared an example to illustrate the potential for confusion. She described 5 variants on the ADAMST17 gene which are associated with Primary Lens Luxation (PLL) and Primary Open Angle Glaucoma (POAG). 4 of the variants are known to be associated with these diseases in 3 hound breeds and one in the Shar Pei. The 5th variant is known to cause PLL in more than 20 (mainly) terrier breeds. It would be quite easy for a breeder to pick a test for POAG that didn’t apply to their breed, for example.
We also have the issue of names changing over time. In Miniature Dachshunds, we originally became familiar with DNA testing for PRA which was refined to Cone-Rod Dystrophy and became known as the cord1 PRA test. This is also now known as crd4-PRA and some people refer to the RPGRIP1 PRA mutation.
Even the way results are reported varies and can cause confusion. One lab describes results of the cord1 test as PRA/PRA, PRA/n and n/n, meaning Affected, Carrier and Clear. Other labs use the terms homozygous and heterozygous. Others refer to Wild Type, rather than Clear.
For some owners, there is still confusion about what a Carrier means and whether their dog “has a disease”. When you add in the potential for a young dog to test as Affected for a very late-onset condition, it’s easy to see how people can end up worrying unnecessarily.
One useful starting point for clarifying the nomenclature is the Online Mendelian Inheritance in Animals (OMIA) database which is a catalogue/compendium of inherited disorders, other (single-locus) traits, and genes in 298 animal species. This currently lists 816 disorders in dogs, of which 533 are potential models for human disorders and around 350 have DNA tests.
Application of DNA tests
Breeders need to know when a test is applicable to their breed and that’s not always clear from the information published by labs. Just because a mutation can be tested for, doesn’t mean it will be clinically relevant in a particular breed. Workshop participants agreed that it would be useful if labs published allele frequency data and details of the country and number of dog samples they had tested.
The IPFD has started publishing “relevance ratings” for DNA tests in their Harmonisation of Genetic Testing database. These are based on the quality and quantity of evidence underpinning a test for a breed and are worth checking out (https://dogwellnet.com/ctp/).
The consensus view at the workshop was that testing labs should not be offering breeding advice on the basis of a single DNA test. They can report the genotype result and explain the combinations of results that would result from different genotype pairings. They can’t, however, provide meaningful advice without knowing other health, conformation or temperament information about that dog or knowing about the wider genetics of the breed.
I also need to remind you of my hobbyhorse: “health-tested” is not the same as “healthy”!
I’m sure the IPFD will be publishing a more detailed write-up of the workshop and the actions arising, so look out for that.
Finally, the Kennel Club has a useful page on its website explaining more about DNA testing and how to use the results. This page also explains how the results of causal, risk-based and linkage tests are recorded.