Audiology Today: We are here with Kathleen Arnos, PhD, who is chair of the upcoming Academy Research Conference (ARC) 2018 on genetics and hearing loss, which is being held on April 18, 2018, the first day of the AAA 2018 Annual Conference in Nashville, Tennessee. Dr. Arnos, thanks for taking the time to chat today; please tell us a little bit about why you choose this topic.

Kathleen Arnos: Sure. Well, I was involved since the inception of the idea for the conference itself, so that means I had a lot of input on the topics and speakers, which was nice. We had a small subcommittee that discussed this over a period of several weeks. I think that we had a really great opportunity to put together an agenda of speakers that addresses a comprehensive range of topics related to genetics that will hopefully be of interest to both clinicians and researchers. It’s such an incredible time in human genetics in terms of diagnostics and new technologies, and the impact on clinical practice is just amazing. This has already started to impact the diagnosis and potential treatment of hearing loss and will have even more of an impact in the next few years. It’s changing so fast.

Completely agree with you! As a person who has worked with clinical studies with adults who have hearing loss, we often go to great lengths to characterize hearing loss, gender, age, and other attributes, but often spend little time exploring a person’s genetic history, because until recently, inexpensive tools have not been available to clinicians or patients. 

We talk about the fact that two persons with same audiogram can have very different experiences with amplification, and yet we don’t consider that their genetic history could provide additional clues as to why there are such large differences across individuals. There are a lot of data sitting right in front of us that could help explain these differences in the lab, and also importantly, in the clinic. 

Exactly, I think that this two-pronged approach of using the traditional tools that we’ve always had in the audiology field (e.g., the clinical diagnostic evaluation tools) can be supplemented by the addition of the “bare-bone” genetics information, such as a person’s family history of hearing loss and how it’s inherited, and include what we call their phenotype (what other characteristics may be associated with the hearing loss). 

Now we have added something new—you might call it “genomic” information with a better picture of a person’s genetic makeup that can have a tremendous effect on identification, prognosis, and treatment. That approach is getting better and better, and we tried to put together a slate of speakers that would reflect all of that, including information about the genomics approach to everything from newborn hearing screening to adult-onset hearing loss and presbycusis.   We wanted to cover a broad range of topics and consider how these new technologies in genetics will impact clinical treatment. 

I couldn’t agree more. I have the agenda in front of me, and it looks like a great slate of topics and presenters. In addition, you have included a panel discussion and plenty of time for audience interaction with the faculty.

So, all these speakers are both clinicians and researchers, so they have that very helpful approach to the topic. We start the day by going back to the basics of genetics. Often, when we do this we start by talking about infants and children with hearing loss because we know a lot about the genetics of congenital and early onset hearing loss. It tends to be more Mendelian, in that inheritance patterns associated with genetic forms of congenital and early-onset hearing loss is often more straightforward. We understand a lot about that, and we use the basic tools of pedigree analysis and what we know about Mendelian inheritance (e.g., dominant, recessive, x-linked) and what we know from population studies that have been done over the last 20–30 years. 

That is, looking at the proportion of children and adults who have hearing loss that we feel is genetic so that we can break it down as to exactly how it is inherited. For example, we know that for congenital moderate-to-profound hearing loss, the most common genetic pattern is autosomal recessive inheritance. That’s an example of some of the basics. We know much less about adult onset or progressive forms of hearing loss, and as we go through the day we’re going to be talking more about that. We will be making a distinction between Mendelian-inherited traits, which as I mentioned encompasses more of the congenital, early-onset hearing loss, versus complex inheritance or a combination of genes and environmental impacts that result in the hearing loss. Complex inheritance is much more important for age-related hearing loss and noise-induced hearing loss, and we will get into that later in the morning. 

Wow, that sounds like a very comprehensive overview of the basics of genetics, for people looking to update their knowledge in these areas. 

Yes, and in addition to the basic genetic approaches (e.g., looking at the “pedigree,” audiograms of family members and possible inheritance patterns), we will also be getting into diagnostic approaches and how that has changed over the last few years, and how we expect it to change in the coming years. For example, for some syndromes that we know are associated with hearing loss, there are very targeted approaches for looking at DNA mutations if the genes for those syndromes have been identified. These targeted approaches to looking for gene mutations can result in a more precise diagnosis for families.

Terrific!

More recent technologies in human genetics fall under the category of “next generation” DNA sequencing, which can involve sequencing the whole genome, or large portions of the genome in families, looking for mutations or changes. These technologies now allow us to test for mutations in many genes at the same time. This is often done when we don’t know much in the pedigree or the phenotype of an individual to guide us in testing. Therefore, we would use a broader approach in next-generation sequencing. The disadvantage of that at the present time is that it is very expensive, but the cost is coming down. 

One of our speakers, Dr. Arti Pandya, will be talking about testing and counseling in the area of “precision” medicine. Suppose that a child who is born with severe-to-profound sensorineural hearing loss has suspected autosomal recessive inheritance based on family history. Right now, the most sensible approach, depending on the ethnicity of that child, is to do stepwise genetic testing for a gene called Connexin 26 (Cx26), because it is common in that situation. Current testing strategies in situations like this start with a targeted approach looking for Connexin genes (Cx26 or Cx30). 

The testing strategy is now changing toward gene-testing “panels” which Drs. Pandya and Morton will discuss in greater detail. With these panels, you can test for many different genes—essentially 100 or more—with one sample. Currently, there are issues with identification of unknown variants, but that’s getting better, and the costs are coming down. Clinicians need to be aware of this testing so that they can talk to families about it and get an idea of where this is going in the future. 

Indeed. I assume that you mean services such as “23andMe.com,” which I see advertised on television quite frequently. It seems like there is tremendous interest in this type of testing, and if I were the parent of a child with hearing loss, I would certainly want to get more information regarding whether this is useful. 

Yes, those forms of “direct-to-consumer” genetic testing do exist and as a matter of fact, more and more families are going to these websites in search of answers. 23andMe, for example, is broad DNA sequencing, where they look for a variety of different things, and they can come back and say, “Oh, you have a genetic change that might make you more susceptible to deep vein thrombosis (DVT), so you shouldn’t ride on airplanes without walking around frequently.”

(Laughing) That’s the story of my life! I feel like I’ve logged many miles walking the aisles of airplanes, as it turns out I am more prone genetically to DVT.

Or they could come back and say that tests indicate that you are more susceptible to colon cancer, so you may want to change your habits, and so on. I have had profoundly deaf adults contact me and say, “I just did 23andMe testing and found out that I have two mutations in this gene called Connexin 26, so what does this mean?” 

Talk about health-care “consumerism!”

Yes, it’s like “Wow!” Previously that type of testing was only available through physicians, and now it’s gone much more mainstream. 

Yes, the megatrend of availability of these sophisticated data to individuals enable them to take a more active role in their health care and lifestyle decisions. If we can use the genetic information to help assist with diagnosis, treatment, and even prevention of specific health conditions, then the future of hearing and balance clinical care may look very different indeed. 

For example, with respect to noise-induced hearing loss, if a person knows that she or he is more susceptible to acoustic trauma, then you can go to greater lengths to prevent that from happening. Furthermore, it can help explain some of those individual differences between temporary and permanent threshold shifts (TTS and PTS) between two colleagues who both work in the same noisy workplace. It’s fascinating how this may evolve in the future.

Indeed. Dr. Lustig, who is on the agenda for late in the morning, will be talking about age-related and noise-induced hearing loss and I think that for clinicians, this represents the majority of the patients that they see on a daily basis. So, having something related to genetics is exciting. 

For sure!

As you say, trying to identify individuals who are susceptible before the fact is intriguing, but that can also be a double-edged sword. For example, with 23andMe, they may come back to you and say that you don’t have this particular mutation that makes you more susceptible to heart attacks, and you decide that you can eat anything you want, when there may be other genes that could still cause problems for you in this area. Regardless, however, these new technologies and what we are learning about complex inheritance involving genes and environmental factors interacting together can really be helpful clinically in the coming future. There’s a lot of work being done, and a lot of new research in these areas. 

Dr. Kelley Dodson will talk about vestibular disorders and unilateral hearing loss. She’s done some research trying to identify some susceptibility genes for those types of disorders, and she will discuss progress in this area during her talk. We have a long way to go, but it’s moving pretty fast!

This sounds like a fantastic agenda, and well worth it for clinicians and researchers to come to Nashville a day early. We’ve only highlighted a few of the sessions; what would you say are the top three overall “takeaways” for attendees of this conference? 

I guess that one of them would be, for clinicians, getting up-to-date facts that allow them to talk to families and individuals with hearing loss a little bit more clearly about genetics, the possible impact, and what they should be aware of that is coming in the future. Communicating this information to families is important, because it can be complicated and a little overwhelming. But, there are things that we see in the newspaper every day, and clinicians need to be able to consider how (and if) they will be able to be applied to the clinical treatment of hearing loss. 

There will undoubtedly be “apps” developed in the future that will make all kinds of promises regarding genetic testing. “Lab on chip” technologies are very promising, but there may also be a lot of confusing or misleading information (e.g., Theranos, which over-promised and under-delivered), and audiologists have the opportunity to provide clarity for individuals and families who are seeking information regarding hearing and balance laboratory testing. Being at least “conversant” about the topic will be highly beneficial, and the first part of the agenda will help with the basic vocabulary and emerging concepts.

Yes, this information is important for pediatrics (when there is a family history) and also when there isn’t a family history of hearing loss. Some clinicians may think that genetics isn’t that important for the patients that they see because the contribution of genetic factors in the etiology has not been clarified, and while that may be true today, it most certainly won’t be the case in the future. 

The information presented will also be important for age-related and noise-induced hearing loss, (which comprise the majority of adult-onset hearing losses) and non-traditional or complex inheritance. I think that this is related to the second major takeaway on research developments that will impact clinical care in the future. A realistic perspective on the ongoing research will be important, and although some may come away a little disappointed that we haven’t progressed further than we have in terms of understanding the genetics of these disorders, but there are lots of changes coming, and they are coming fast. 

Yes, and speaking as a member of the Baby Boomer generation that has acquired hearing loss, in part, from a combination of aging, noise exposure, and genetic factors, I would certainly leave no stone unturned regarding diagnosis and treatment of hearing loss, including seeking out genetic counseling based on my phenotype. Much of this might not be possible yet, but if there are any circumstances that the practitioner should be aware of, this meeting would be a great place to convey that information for clinicians. What’s the last take-away item?

I think that it would be that as we look toward the future, what can we expect? I’ve asked Dr. Cynthia Morton, who is the last speaker, to talk about therapeutics. Anybody who reads the newspaper (carefully) has come across the topic of “gene editing” or CRISPR (an acronym for a technique used for gene-editing), which is a type of genetic engineering in which DNA is inserted, deleted, or replaced in the genome of a living organism using engineered nucleases or “molecular scissors.”

The technology is incredible and it is going to be helpful for many things, including cancer diagnostics and even for identification (and treatment) of viral infections. I think that a good takeaway pertains to the status of gene-editing and what are the “pros and cons” of the technique—it’s a very controversial topic. A few months ago, a lot of us were surmising that there weren’t a lot of applications related to hearing loss yet, but people are starting to publish about experiments in animals that may become clinically applicable.

As they say, objects in the mirror may be closer than you think.

And that’s a little scary.

Well, I look forward to seeing you and hearing from you and the other faculty in Nashville at the Academy Research Conference. Registration is open through www.AcademyResearchConference.org. 

Thank you again, for taking the time to speak with us. 

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