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Genetic Counseling, Connexin Genes, and the Role of the Audiologist: Interview with Ali A. Danesh, PhD 

Douglas L. Beck, AuD, speaks with Dr. Danesh about genetics and hearing loss.

Academy: Good morning, Ali. Thanks for your time today.

Danesh: Hi, Doug. My pleasure, nice to see you again.

Academy: Ali, I should note that you presented a rather amazing talk here at the Florida Academy of Audiology meeting (August 2009) titled “What Should AuD Docs Know About AuD Genes.” So that begs the question…what should we know?

Danesh: Well…essentially, although we don’t want to be geneticists, audiologists do need to be conversant in the basics, to best advise patients with regard to hearing loss. As you may know, we previously assumed humans had 100,000 genes. In fact, it now appears we have some 25,000 genes.

When we consider hearing loss affects some 70 to 75 children per thousand, when we include profound sensorineural hearing loss, unilateral hearing loss, those with minimal and mild hearing loss, syndromal origins, CMV and more. We know that some 70 percent of genetic hearing losses are non-syndromic and 75 percent of those non-syndromic cases are autosomal recessive conditions that are clearly genetically based—so genetics plays an enormous role.

Academy: Excellent point, and I think you noted that about 15-20 percent are autosomal dominant, and perhaps 1-2 percent are X-linked. If I recall, you had some excellent starting points in your talk and I’d like to just list a few—the Genome project has substantially added to our knowledge of human genetics, we share some 98 percent of our genetic material with monkeys and apes, we have fewer genes than anticipated, humans produce a wider variety and quantity of proteins than other animals, and some 200 human genes have come about from bacteria.

Danesh: Right. Those are each important points, and they indicate that so much of our knowledge and understanding about these topics is quite new, having only been confirmed and documented in the last few years. Therefore, as we approach genetics and audiology, like many other things, the topic and our understanding of it is “a work in progress.” For example, we now know that across all 46 chromosomes, there are genes that can affect hearing, and even in Y chromosomes there are genes that can contribute to hearing loss.

Academy: Yes, it really is amazing. I recall you mentioned “pseudogenes,” which are essentially “junk DNA” yet they contain all the raw materials from which evolution occurred. This is fascinating, Ali. Would you please review the issue of “molecular screening tests?”

Danesh: Yes, of course. The issue is that we have molecular tests for four important causes for late onset pre-linguistic hearing loss (DFNB1, CMV, PDS, and the mt 12S rRNA A1555G mutation). If these were added to the molecular battery of tests currently employed, we would detect more than half of all infants with normal hearing at birth who are very likely to develop clinically significant hearing loss by the age of four years.

Academy: Ali, the concepts, tests, and ideas you’re sharing are fascinating, perhaps even startling. However, it does get me thinking that many audiologists reading this are thinking “Wow! But how does this impact me as an audiologist?”

Danesh: Sure, well that’s a pragmatic and interesting point. The way I see it, this information is essentially of maximal value when we counsel patients. I do not offer genetic counseling, but I do talk about genetic counseling and I do refer the patients to genetic counselors, and further, I can provide the patients with very inexpensive genetic lab-test screening tools for them to employ, if they so choose.

Academy: Do you do this with all of the parents?

Danesh: Yes, if I suspect their child has a genetic component to their hearing loss, I believe referring the parents to a genetic counselor is reasonable and is our responsibility…and again, the a great number of children with hearing loss will have a genetic component—so we should have an understanding and command of the basics, so as to best help guide and direct the parents with regard to their access to information. For example, if I am working with a mom who has a child with Down’s syndrome, I might talk about the factors that pre-dispose the child to Down’s syndrome if the mom inquires about that, or perhaps a little discussion about chromosomal abnormalities. Of course, I would address the child’s auditory system and the tests we can do to determine the current hearing status, as well as to discuss the general trends and options available with respect to amplification, aural rehabilitation, and related matters so as to maximize the child’s auditory opportunities.

Academy: Ali, can you give me a quick tutorial on Connexin genes?

Danesh: Sure. Connexin genes are the major reason for non-syndromal autosomal recessive hearing loss, which is why it has appeared in our literature increasingly over the last few years. It is very common in certain populations across the world and is found generally in people of eastern European backgrounds.

There are two types of Connexin deficits—(1) Connexin 26 and (2) Connexin 30. The numbers 26 and 30 refer to their molecular weights. Connexin 26 is much more common and it is a six-sided protein that fills in the gap junctions between the cells. The gap junction is a major component in an electrical synapse and it is the simplest type of electrical communication between two neurons when there is a size match, and the information flows uni-directionally, meaning only in one way. Therefore, when there are failures in Connexin genes, many functional and developmental abnormalities can occur, such as hearing loss. Additionally genes such as alpha tectorin, which is expressed in stria vascularis are very important, considering that the tectorial membrane is essential for mechanoelectrical transduction by the organ of Corti.

Academy: Please explain the DFN terminology?

Danesh: Sure. Well, DFN just stands for “deafness.” Therefore, DFNA means deafness due to an autosomal dominant condition, DFNB is autosomal recessive, DFNX is X-linked and DFNM means deafness due to a modifier gene. There are also numbers after the DFN letters, and those numbers refer to the order in which the gene was discovered or recognized.

Academy: This information is fascinating. What about the future, where is all this going?

Danesh: Well certainly none of us can predict the future, but we do know that we’re all looking for ways to end hearing loss, particularly in children….and so the outcome of all this might be the application of gene therapy, to correct errors in gene coding and sequencing that cause hearing loss. Gene therapy has already been applied to cystic fibrosis, and gene therapy has been applied to Parkinson’s, too. However, this is very difficult and time intensive work, and there are no promises of results in the near future.

Academy: I understand….and so gene therapy occurs through carrier viruses?

Danesh: Yes, that’s right. The viruses used are “adenoviruses.” The adenovirus could contain a corrected DNA injected into virus, a “carrier virus” so to speak, and that would be injected into the body, and that could potentially affect the cochlea.

In guinea pigs, this has been successful with regard to restoration of hearing and hair cell regeneration, and it’s been successful some 70-80 percent of the time, but guinea pigs are not humans, and there’s a long way to go before we make progress with regard to gene therapy in humans. But eventually, if we knew a developing fetus had a genetic disorder associated with hearing loss, it might be appropriate to try gene therapy to avoid the likelihood of hearing loss in that child.

Academy: Fascinating. Thanks for your time, Ali.

Danesh: My pleasure, Doug. Thanks for your interest.

Ali A. Danesh, PhD, is an associate professor, Department of Communication Sciences and Disorders, and Department of Biomedical Sciences, Florida Atlantic University, Boca Raton, Florida.

Douglas L. Beck, AuD, Board Certified in Audiology, is the Web content editor for the American Academy of Audiology.