The Genetics of Hearing Loss

Lustig, Lawrence R., MD
Howard W. Smith Professor and Chair
Department of Otolaryngology-Head & Neck Surgery
Columbia University College of Physicians and Surgeons
NewYork-Presbyterian/Columbia University Irving Medical Center
New York, NY Also by this Author 

Since the sequencing of the human genome, we have made major advances in our understanding of auditory physiology. There have been state-of-the-art developments in the diagnosis of hearing loss, and research continues to advance the use of gene therapy as a potential approach to correct genetic forms of hearing loss.

In this paper, one of the nation's leading experts in hearing loss, Lawrence Lustig, MD, explains how the genetics of hearing loss has led to a better understanding of the anatomy of the ear and how we hear, as well as its impact on patient management, treatment and research.

 

Genetic Hearing Loss

According to the Centers for Disease Control and Prevention, 50% to 60% of hearing loss in infants is due to genetic causes.1 Ninety-five percent of newborns identified by newborn hearing screening as having hearing loss are born to hearing parents, obscuring the fact that the majority of newborns with hearing loss have a hereditary cause for their hearing loss.2 Analysis of family history data from school-aged children in the United States estimated that up to 60% of educationally significant congenital and early-onset hearing loss is caused by genetic factors.2

According to Dr. Lustig “With [purely] genetic forms of hearing loss, there's a problem in the underlying genetic code that leads to some type of instability of the inner ear.” Genetic hearing loss could be at birth or could be hearing loss as you age, early in life or even later”

 

Studying How We Hear

“Using genetics, various types of experiments have led us to a much better understanding of how the ear works,” notes Dr. Lustig. “Using an animal model of genetic hearing loss, with a transgenic mouse that can’t hear, we can identify the gene responsible for hearing loss, look at the ear, and understand what that gene does in the ear.

“I'm fascinated about this whole field because of what it tells us about how we hear. Once we know which are the defective genes and how they impact hearing, we can start designing treatment strategies.”   

Understanding the defective genes in mice has added to our grasp of human genetics. This information has advanced testing for diagnosing the genetic etiology of a patients’ hearing loss.

 

When is Genetic Testing Indicated?

When to test for genetic hearing loss is an evolving topic. Dr. Lustig explains. “At this point, you can argue that genetic testing is never indicated, and you can also argue that it's indicated in every single case. One challenge is that, in many cases, insurance companies don’t cover the cost, so that's out-of-pocket expenses for families. And we're not at a point where the answer to a genetic test will fundamentally change how we treat a child. At the end of the day we're still going to treat them based on their hearing loss.

“Now, what genetic testing may do,” notes Dr. Lustig, “is when there is partial hearing loss, it will tell us if there are any other medical conditions we need to be concerned about and monitor closely, such as vision or kidney problems or heart problems.  Genetic testing may also provide an indication of what the rate of that hearing loss will be over time. And, in some cases, it might inform us of how well a patient might do with an intervention like cochlear implants.  Most people with genetic forms of hearing loss do well with cochlear implants. So knowing may prepare a family that their child may benefit from a cochlear implant at some point down the road and not to wait too long, knowing it's inevitable.”

Dr. Lustig continues, “Another very tangible benefit for testing when a child is born with a hearing loss is understanding the genetics of the disorder. With this information we can offer genetic counseling3 to the parents. Counseling can inform the family about the risks for future children having hearing loss and the risk that they may pass those genes down to their children. I also discuss the risk that their child may, if they're not already deaf, continue to lose hearing over time and at what rate, and what they can expect going forward. This provides comforts to families knowing what to expect and how they can prepare.”

“Lastly, what I think is the most important aspect of genetic testing is the use of the data in developing molecular treatments for hearing loss. We're doing a research study now where we’re doing whole exome sequencing (WES) to see what we find and if we can correlate what we see genetically with what we see clinically. There is hope that there will be future treatment for those with genetic forms of hearing loss.”

 

Choosing a Gene Panel

“In terms of genetic testing, everybody is doing something a little bit different,” which can complicate choosing the right panel for your patient.  Dr. Lustig recommends using a CLIA-certified lab that has a long track record. “I personally believe that the best approaches involve looking for the most common genes first, because that's going to be the area where you're going to most likely get a hit. You want to be able to capture every single way that that gene may be abnormal. Not all gene tests are created equal, but testing for the most common genetic abnormalities up front is important, while knowing that there's going to be a significant number of people who don't test for any of those genes.”  There are choices in the market for small and large genetic panels, as well as whole exome sequencing.  “That just tests all of the active genes in the body, the ones that are actively making protein. You're going to capture more abnormalities with this technique, but you may not be exactly sure what that data means. Testing gets progressively more complicated the deeper you go.4 Currently we don't have a really good understanding of all of the genetic variations.”

 

Setting the Stage for Future Therapies

Dr. Lustig's research focuses on understanding the molecular mechanisms of inner-ear function and gene therapy approaches for hearing loss. In his lab, he is using gene therapy to correct the hearing loss in several animal models of inherited deafness.

Dr. Lustig explains, “We have to be able to get the gene into the ear, using viruses to infect cells with DNA. We pull out all the bad DNA in those viruses that cause disease, and we load it up with the gene that is missing or defective. And then we cause the cells that are making the bad gene now to make good genes, and use that to try to correct the hearing deficit.  There have now been a number of attempts in mouse models of deafness that have actually worked. In some cases it worked quite well.”

The overall goal of these studies is to translate these research advances into a human therapy that will one day offer a cure for genetic deafness.

“We're at a stage where a number of companies are trying to figure out how to translate this back into humans. I think we're just on the cusp of really exciting things.”The Genetics of Hearing Loss

Since the sequencing of the human genome, we have made major advances in our understanding of auditory physiology. There have been state-of-the-art developments in the diagnosis of hearing loss, and research continues to advance the use of gene therapy as a potential approach to correct genetic forms of hearing loss.

In this paper, one of the nation's leading experts in hearing loss, Lawrence Lustig, MD, explains how the genetics of hearing loss has led to a better understanding of the anatomy of the ear and how we hear, as well as its impact on patient management, treatment and research.

 

References:

  1. Centers for Disease Control and Prevention. Genetics of Hearing Loss https://www.cdc.gov/ncbddd/hearingloss/genetics.html
  2. Alford RL, Arnos KS, Fox M, et al. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med. 2014 
  3. Shearer, A.E.; Hildebrand, M.S.; Smith, R.J.H. Hereditary hearing loss and deafness overview. In GeneReviews((R)); Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mefford, H.C., Stephens, K., Amemiya, A., Ledbetter, N., Eds.; University of Washington: Seattle, WA, USA, 1993. 
  4. Boyd SD, Galli SJ, Schrijver I, Zehnder JL, Ashley EA, Merker JD. A balanced look at the implications of genomic (and other “omics”) testing for disease diagnosis and clinical care. Genes. 2014;5:748–66.

 

 

Expert Contributor

Lawrence R. Lustig, MD 

Howard W. Smith Professor and Chair

Department of Otolaryngology-Head & Neck Surgery

Columbia University College of Physicians and Surgeons

New York-Presbyterian/Columbia University Irving Medical Center, New York, NY


Released on Friday, June 22, 2018