On the Genetic Trail of Hearing Loss Genetic testing can help identify the underlying causes and management of hearing loss. Sami Amr, a clinical molecular geneticist, led a recent Web chat touching on related complexities and challenges, including cost, ethics and interpretation. The Leader listened in. Overheard
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Overheard  |   February 01, 2015
On the Genetic Trail of Hearing Loss
Author Notes
  • Sami Amr, PhD, is an American Board of Medical Genetics-certified clinical molecular geneticist. He is director of the Translational Genomics Core at the Partners Healthcare Center for Personalized Genetic Medicine in Boston and assistant director at Partners Healthcare’s Laboratory for Molecular Microbiology. He is involved in development, validation and reporting of clinical genetic tests across a variety of disease areas, with a focus on hearing loss. samr@partners.org
    Sami Amr, PhD, is an American Board of Medical Genetics-certified clinical molecular geneticist. He is director of the Translational Genomics Core at the Partners Healthcare Center for Personalized Genetic Medicine in Boston and assistant director at Partners Healthcare’s Laboratory for Molecular Microbiology. He is involved in development, validation and reporting of clinical genetic tests across a variety of disease areas, with a focus on hearing loss. samr@partners.org×
Article Information
Hearing Disorders / Audiologic / Aural Rehabilitation / Special Populations / Genetic & Congenital Disorders / Overheard
Overheard   |   February 01, 2015
On the Genetic Trail of Hearing Loss
The ASHA Leader, February 2015, Vol. 20, online only. doi:10.1044/leader.OV.20022015.np
The ASHA Leader, February 2015, Vol. 20, online only. doi:10.1044/leader.OV.20022015.np
Bridget Gonzalez: You used the abbreviation STRC. What does it stand for and can you give a further explanation? Thanks.
Sami Amr: STRC is the gene name for steriocillin. This is one of the genes that we test for in patients with nonsyndromic hearing loss and we found that large deletions in this gene are common pathogenic variants in individuals with nonsyndromic autosomal recessive hearing loss.
Gonzalez: Is there a reason that stereocillin sounds like it would be an antibiotic—penicillin, amoxicillin, etc.—or is it just an unfortunate coincidence?
Amr: I think that’s just an unfortunate coincidence. Stereocillin refers to the stereocillia, which are important mechanical components of the inner ear hair cells.
Deborah Hayes: Can you please suggest the information that clinicians, including audiologists and otolaryngologists, can provide that will be helpful in interpreting genetic test results?
Amr: There are several websites, such the Online Mendelian Inheritance in Man (OMIM) and GeneReviews, that provide information on the gene/disease associations and particular variants within genes that can help explain the relationship between particular variants and genes to hearing loss—whether it be syndromic or nonsyndromic.
However, one of the difficulties of interpretation is assessing novel variants seen in individuals—and most variants will be unique to a family or an individual—and, therefore, we need to dig deeper to find out how any particular variant may be related to the hearing loss. To do this, we use a number of pieces of evidence, such as the clinical picture (does it match with the type/severity/onset) of hearing loss associated with a gene; gene- and protein-specific information, such as domains that are intolerant to variation as well as the pathogenic variant spectrum in that gene; and the frequency of the variant in normal individuals and in affected individuals.
And this requires a collaborative effort from the clinic and the lab; part of my job, as a clinical molecular geneticist, is to work with clinicians and audiologists to make sense of genetic findings in the context of the clinical manifestations seen in hearing loss patients.
Vaibhavi Dharkar: In a syndrome with progressive hearing loss, will a gene show mutation even if the HL has not represented itself?
Amr: Yes, in any type of hearing loss, whether it is congenital, late-onset, and/or progressive, the mutation—or what is often now referred to as variant—can be detected before the HL manifests. This is because these variants are present as germline mutations and are found in every cell in the body and are inherited through the sperm or egg of the parents. This highlights the clinical utility for genetic testing: the ability to predict the onset of additional symptoms or predict the progression of disease. For example, part of the panel we use also includes genes for Usher syndrome, where individuals may come in for testing for nonsyndromic hearing loss because the retinitis pigmentosa has not yet been detected/expressed, but we’ve identified mutations in Usher genes that will affect how they will be managed in the clinic.
Ellen Mastman: Are there ever mutations during growth and development in an organism after it is born (or hatched) that may affect development later on?
Amr: Yes, there are scenarios where this is possible in genetics; however, this is less common in the hearing loss world. We refer to a mutation that occurs after an organism is born as a somatic mutation; this type of mutation begins with a single cell in the body and increases as that cell replicates. However, our bodies have a way to identify these mutations during DNA replication and “fix” or eliminate them. But when the DNA-editing machinery doesn’t work or is overwhelmed, those cells begin to replicate and may behave erratically, which would eventually cause tumor growth or metastasis.
Dharkar: How can different testing facilities share their data? Are there any data banks that are collecting this information?
Amr: Yes, absolutely. There are several initiatives for data sharing from a variety of sources: research, clinical, molecular laboratories. One such effort that our lab is involved in is the ClinVar database, a publically available database that encourages different labs to submit their variants and their variant classifications (for example, are these variants pathogenic or benign), and what clinical features are seen in the individuals that have these variants.
In addition, this particular database provides a rating for the variant classification. For example, if a variant was only seen and classified once, it would get a one-star rating. But if it was seen in multiple clinical diagnostics laboratories that all agree on its classification, it may receive a two- or three-star rating, to reflect a higher confidence in the community on this classification.
There are other databases, such as dbSNP, Exome Variant Server and many disease-specific databases out there as well. While these databases are useful to tell you if a variant was seen in the general population or in other individuals with hearing loss, you have to be careful when using these databases because the classification system or assessment process for variants in other databases may not be as reliable as in ClinVar.
Tina Posch: As genetic testing becomes more affordable and clinically beneficial, what controversies or ethical dilemmas do you foresee down the road?
Amr: Good question and an important issue that people in the clinical genetics field are trying to address. One of the main ethical or controversial issues is related to the return of results. For example, if a patient comes in for hearing loss testing, and we identify a mutation that does not address the hearing loss but is associated with a different disease, do we return that information to the patient? This is compounded if this disease is something untreatable.
The argument is that some people do not want to know if they will develop Huntington’s disease because there is no cure for it or treatment. On the other hand, if we do identify mutations for a disease that can be managed or treated, which diseases should make it on that list? It’s still an ongoing debate within the field and I think it will take some time to identify what will be best for clinicians and patients in terms of data return. Another concern with patients is related to discrimination based on genetic information related to employment or health insurance—however, this has been addressed by Congress through several laws that prohibit the use of genetic information for this purpose.

One of the main ethical or controversial issues is related to the return of results. For example, if a patient comes in for hearing loss testing, and we identify a mutation that does not address the hearing loss but is associated with a different disease, do we return that information to the patient? This is compounded if this disease is something untreatable.

Gonzalez: In your presentation you said that, “You need to do a segregation analysis of family members.” Do geneticists want to do analysis of all family members who will volunteer, or—because of the cost—do they focus on only those members who have a hearing loss?
Amr: I always say the more segregation information we can carry out, the better. For laboratories, being able to do segregation analysis for variants of unknown significance is very helpful and many labs offer this for free for any family members. The cost of segregation analysis for one or two variants is a fraction of the cost of the entire panel and many labs are willing to take this cost on so as to provide a better report. However, usually segregation analysis in affected family members will provide more useful information to support a classification.
Mary Violanti: In practice, is genetic testing for hearing loss usually only requested for pediatric patients? For adult patients with acquired hearing loss and/or vestibular problems, any red flags that suggest a genetic test panel would be a good idea?
Amr: From the clinical laboratory side, we do see more genetic testing being requested for pediatric patients, often to follow up on a newborn screen and/or a family history of hearing loss. I think a reason for this may be related to the fact that congenital hearing loss has a greater chance of having a genetic cause and is often more severe than adult-onset hearing loss. However, there are several genes that cause late-onset hearing loss, with variable penetrance and expressivity, and may manifest with additional clinical features. I discussed KCNQ4 in the presentation, which manifests with a later-onset hearing loss and is inherited in an autosomal-dominant fashion; genetic testing in this case can inform family members of their risk for developing hearing loss, progression of disease, and risk for children.
Another one that comes to mind is variants in WFS1 that cause autosomal-dominant hearing loss that has a later onset and may affect mid-frequencies or, more commonly, low frequencies. However, in some families, variants in WFS1 may also cause additional phenotypes such as late-onset diabetes and/or optic atrophy.
And for individuals that inherit two WFS1 mutations from both parents, they may manifest with Wolfram syndrome, which is characterized by juvenile-onset of diabetes, optic atrophy and hearing loss. So there is certainly a lot of utility in testing if genetics is suspected in individuals with adult-onset hearing loss.
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February 2015
Volume 20, Issue 2