The Current State of Testing for Early Adult Onset Deafness (EAOD)

ABCA Health & Education Foundation, Inc. — September 2019

The mutation that causes EAOD has not been discovered yet. The scientific team working on the research project that ABCA HEF has been funding — headed by Dr. Hannes Lohi at the University of Finland and Dr. James Mickelson at the University of Minnesota — has been working intensively to identify this causative mutation for the last three years, and has greatly narrowed the region in which it is expected to be found, but their work is still ongoing.

In the meantime, they have shared information with Genoscoper Laboratories in Europe, and Genoscoper’s parent company Wisdom (Mars) in North America, to enable those testing labs to offer what is called a “marker test” for EAOD. A marker test is not a test for the causative mutation. Rather, it is a test for markers — in this case a set of four markers — that are so closely linked to one another in the dog’s genetic material that they are always inherited together. There is good reason to believe that the not-yet-discovered causative mutation is also tightly linked to those markers, because so far all the dogs with EAOD that have been tested have carried two copies of the marker set. But the reverse of that is not true — all the dogs that carry two copies of the marker set do not suffer from early adult deafness.

The ABCA HEF does not endorse this marker test, nor do we encourage people to test at this time, before the causative mutation is found. But at the same time, we are not telling people not to test. The test does have some significant benefits, especially for someone whose dogs have deafness somewhere in their pedigree and who must make a breeding decision in the immediate future or who is considering buying or beginning the training of a young dog with deafness in its pedigree. The presence of deafness in a pedigree greatly increases the chances that the marker set will be associated with a causative mutation. The decision whether to purchase the test at this stage is yours alone, but in making that decision here are some factors we think you should consider.

We believe the current data strongly suggest that a CLEAR result on the test means that the tested dog does not carry the causative mutation for EAOD.

However, we believe there is not enough evidence to conclude that a CARRIER result, or an AT RISK result, means that the tested dog does carry the causative mutation. Remember, this is not a test for the mutation itself, as the CEA test is. In the CEA test, an Affected result means that your dog is carrying two copies of the mutation that causes CEA, and will pass one copy on to its offspring. In the EAOD test, an At Risk result does not mean that your dog is carrying two copies of the mutation that causes early deafness. It only means that your dog is carrying two copies of a set of markers that do not cause EAOD but have been shown to be associated with some increased risk that the dog who carries them will have EAOD. How great is that increased risk? We have no idea. In fact, it is entirely possible, from the current state of our knowledge, that your At Risk dog is not carrying the causative mutation at all.

Based on statistics from dogs in the research database, estimates have been published that up to 35% of Border Collies may carry one copy of the marker set, and close to 8% may carry two copies. This is notably higher than would be expected based on the percentage of dogs that display EAOD. It may simply be that the marker set is frequently found without the causative mutation. However, it may also be that the sample groups used were not representative of the Border Collie population as a whole, but were skewed by the disproportionate inclusion of dogs already suspected of deafness. It could also be that expression of the causative mutation is affected by the actions of yet-to-be-discovered modifier genes which may, for example, act to delay
the onset of deafness to an age where old-age deafness would be expected or beyond the lifetime of the dog.

But whether or not these prevalence figures are inaccurate to some extent, they illustrate the vital importance of not removing so-called Carrier dogs from breeding. If this test were to cause breeders not to breed “Carrier” dogs, we would be removing 1/3 of our population from our gene pool, without regard to working ability, and in a situation where for all we know they may not be carrying the causative mutation at all. That loss of good working lines and genetic diversity would be devastating, and is our biggest fear regarding use of the marker test. Carrier results from the currently available tests should not exclude dogs from being used for breeding. If your dog’s test results come back “Carrier,” we strongly recommend that you simply use the test to make sure the dog you breed him/her to is Clear. Do not just exclude your dog from breeding.

We have been asked whether the researchers have submitted their results for peer review and publication. The answer is that so far they have not. We have a written agreement with them that they will do so, but the agreement does not specify at what stage of the research this must be done. It is unlikely they will do it before the causal mutation itself is found, since that is what the project was designed to accomplish and that will be the culmination of their work.

We have also been asked why Genoscoper/Wisdom only offers this test as part of a panel of tests, rather than as a stand-alone, less expensive test. In all likelihood they are doing this (a) because it is better for their research goals, since this way they can test for the presence of many variants of interest across a large number of dogs and breeds, which can be very informative for researchers, and (b) because it is better for their marketing goals if people come to view them as a one-stop shop for all dog testing. Whatever we may think of this, ABCA HEF has no control over it. We do have assurance that the results of the study will be published once the causative mutation is found, and one of the purposes of insisting on that was so that other testing companies can develop and offer their own tests, and competition among them should bring prices down and offer dog owners a variety of options.

And we have been asked if Genoscoper/Wisdom will provide those who buy the test now with updated results at no additional cost, once the causative mutation has been found. This is a question we have asked several times, and never received an answer. This leads us to believe that they will not do so, which is a reason why dog owners who have no immediate need for testing might want to put off having their dogs tested for the present.

In addition to the Genoscoper/Wisdom test, an Australian testing company called Orivet is also offering a DNA marker test for EAOD. The test Orivet is offering is a stand-alone test for a single marker, one of the variants discussed in the 2012 PLOS publication by Yokoyama, et al. According to Dr. Lohi, this is not one of the four markers being used in the Genoscoper/Wisdom test, and it does not correlate well with their marker set. Dr. Lohi’s team has found dogs that do not carry the marker set Genoscoper/Wisdom is using, but are heterozygous for the marker Orivet is using. Such a dog would be classified as Clear under the Genoscoper/Wisdom test, but as Carrier by the Orivet test. Again, neither the Orivet test nor the Genoscoper/Wisdom test is a test for the causative mutation for EAOD and, therefore, some At Risk or Carrier results may be false positives for EAOD.

EAOD Research Project Report – September 2018

The ABCA Health & Education Foundation has received a progress report from Dr. Hannes Lohi’s team studying EAOD, which says that they have essentially identified the causal gene and its likely causative variant. They need to complete some additional experiments to validate their conclusions prior to a peer-reviewed publication, but they hope to be able to submit their work for publication before the end of the year. That doesn’t mean that the work will be published by then — the peer review process can sometimes be lengthy — but submission for publication is very important. It not only provides for evaluation of their work by other researchers, but also, once their results are published, it will be possible for any testing laboratory to develop and offer DNA tests for EAOD based on this research. Both the researchers and ABCA HEF agreed at the start that publication was essential, for the advancement of research and to permit competition to keep test prices lower.

In the meantime, based on the results they’ve achieved, the research team has begun the process of developing a gene test in collaboration with a very large, well-regarded testing company. The intent is to ensure that a test is available for veterinary diagnostic purposes and breeding decisions as soon as possible. The best current estimate for availability of the test is January 2019. If the test becomes commercially available from this company before other companies have been able to bring a test to market, there is a side benefit for us — we will be able to get data that will best show the prevalence of EAOD in our dogs. Right now, a certain percentage of our dogs carries the EAOD mutation, but we have no way of knowing what that percentage is. It’s the portion of the dogs who show up as Affected, Carrier or Normal when the test first becomes available that will give us this information. Later on, after the test has been on the market for awhile, these figures will gradually become less and less informative about the prevalence of the EAOD mutation, because more people will tend to test only suspect dogs, so the data will be skewed. Early on is when the sample of dogs being tested will be the most random, and will give us the best estimate of the true percentage of Carriers and Affecteds in our breed right now. That knowledge is very important in developing recommendations for breeding.

Dr. Lohi and his colleagues intend to continue and broaden their study to better understand this complex disease. Additional clinical studies will help in understanding its dimensions, including variations in age of onset and manifestations. For example, it is not yet certain that EAOD is 100% penetrant. There may be cases where dogs who carry two copies of the causative mutation do not become deaf. (This is similar to CEA. CEA has an autosomal recessive mode of inheritance, yet there are cases (often called “go normals”) where a dog who carries two copies of the causative mutation, and therefore will pass that mutation on to its offspring, does not show symptoms of the disease. It’s not yet known whether the same may be true of EAOD, or if so, how frequently this occurs.)

Dr. Lohi and his colleagues ended their report by thanking the ABCA Foundation for our “very helpful” and “much appreciated” support for this research. We in turn thank them for their hard work and the good results they have been able to achieve.

BAER Testing DNA Collection 2017 Finals

BAER Testing and DNA Sample Collection at the 2017 Sheepdog Finals

As a service to ABCA members and to advance.research into the genetic conditions that affect our Border Collies, the ABCA Health & Education Foundation will be offering free hearing tests for ABC registered dogs at the USBCHA Sheepdog Finals this year, and will also be collecting DNA samples to be used for deafness research and to be stored in our DNA bank. The BAER and sample clinics will take place on Sept 27-29 (Wednesday, Thursday and Friday) at the trial site. BAER testing will be done by Dr. Colette Williams, whose credentials are excellent and who was the tester at last year’s BAER clinic. We hope that our members — especially owners of dogs with suspected hearing loss, from lines known to have hearing loss, or those from previous finals clinics recommended for follow-up — will take advantage of this BAER testing opportunity.

To participate, please fill out a copy of this questionnaire/consent form for each dog and send it, together with a copy of the dog’s pedigree, to Eileen Stein. The documents can be sent either by email (Eileen Stein) or by postal mail (PO Box 41, Shady Side, MD 20764), so long as they are received by September 21. If you are unable to submit the documents in advance, please bring two copies of each with you to the clinic. Dogs will be entered on the BAER list when paperwork is received and will need to submit a DNA sample at the clinic.

All health information submitted to the Foundation will be treated as strictly confidential, and will not be used in any way that would disclose identifiable information or testing results to anyone but the dog’s owner.

EAOD Project Update

As of the close of 2016, the HEF has acquired DNA samples from 400+ North American dogs, over 75 of whom have been BAER tested. Whole Genome Sequencing is currently being conducted on 8 affected dogs.  The sequencing should be completed within the next two weeks, after which the data will be analyzed, with the Genome Wide Association Study to follow, based on the results of the WGS.  Our sincere thanks go out to all of you who have contributed samples, pedigrees, information and financial support to this ongoing effort. 

Samples Needed for Border Collie DNA Bank

The ABCA Health & Education Foundation (HEF) is moving forward with its mission to bank Border Collie DNA and to support important research into the causes of genetic diseases in Border Collies.

We will be fully sequencing the genomes of 10-20 Border Collies! The complete genetic information from these dogs will become the initial foundation of our DNA bank. In this first phase of collection, we want to obtain samples that can be used to support ongoing research into the two most critical genetically linked diseases in our breed — early adult onset deafness (EAOD) and epilepsy. But the sequencing information can also be used for research into other disorders as well, now and into the future. And by fully sequencing dogs who are only distantly related, we can expect to capture the widest possible array of gene variations across the spectrum of our breed.

We specifically need dogs that fall into the following categories:

  • Dogs affected with EAOD who went deaf between the ages of 2 and 8, and are as unrelated to each other as possible.
  • Dogs with idiopathic epilepsy who are as unrelated to each other as possible.
  • Dogs from lines with no known incidence of epilepsy, and no known incidence of EAOD.

These dogs must be over the age of 8 with no hearing loss, and as unrelated to each other as possible.

And now for the hardest category to find: Dogs unaffected by EAOD, who were bred to dogs that did become affected with EAOD, and who produced at least 8 pups from such mating(s) (in one or more litters), all of whom reached the age of 8 with no hearing loss. These dogs will of course be old now, and there won’t be many of them, but they are almost certain not to be carriers of EOAD, and so they are the ideal controls for research. If you have such a dog, please contact us! If you have a dog that comes close to meeting these criteria, please contact us too. And if you know someone with such a dog, please urge them to contact us.

If you have a dog that fits into any of these categories, please go to https://bordercolliefoundation.org/get-involved/genome-sequencing/ for details of how to propose your dog for inclusion in this project. In order to achieve as much diversity (unrelatedness) as possible among the dogs to be sequenced, we will need your dog’s ABCA registration number plus permission to access his/her pedigree information. Please give details if your dog has been BAER tested. All submissions and results will be kept confidential. There will be no charge for participation, and the HEF will pay for any BAER testing that may be necessary.

Best of all, if your dog is among those chosen for sequencing, you will receive a copy of his/her whole genome, at no cost to you!