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Genetics of Hearing Loss

Rudman, Jason, MD; Liu, Xue Zhong, MD, PhD, FACS

doi: 10.1097/

Dr. Rudman, left, is the clinical chief resident at the University of Miami Department of Otolaryngology-Head and Neck Surgery. His research encompasses genetic hearing loss with an emphasis on underserved populations. Dr. Liu, an internationally renowned surgeon-scientist, is the Hotchkiss Endowed Chair in Otolaryngology and Leonard M. Miller professor of otolaryngology, human genetics, biochemistry, and pediatrics, and vice chairman of otolaryngology at the University of Miami.

Hearing loss (HL), as a broad diagnostic term, affects upwards of 360 million people worldwide.1 However, the etiologic diversity of HL proves to be a challenge to efficient diagnosis and treatment. Half of congenital HL is genetic, with more than 400 known syndromes with HL as a feature and more than 100 known genes that have HL as the only clinical manifestation. Despite these daunting figures, the importance of obtaining a specific etiology for an individual's genetic HL significantly affects how a practitioner counsels, monitors, and treats each patient. Fortunately, audiology is poised to take advantage of recent advances in fast and inexpensive genetic testing technology (e.g., next-generation sequencing), improvements in data analysis, and widespread use of electronic health records (EHR).

Most cases of congenital HL are identified soon after birth via newborn hearing screening (NBHS). However, many HL cases only become apparent later in life due to the expression of late-onset HL mutations or following an environmental insult, like antibiotic use or head trauma, in the genetically predisposed patient. The implications of missed and delayed diagnoses indicate room for improvement, providing a great opportunity to take advantage of the newest ideas and tools of genetic testing. An HL-causing mutation will be present at (and before) birth, even if the HL itself is of progressive or delayed onset. A genetic screening panel that incorporates a population's common HL genes could therefore be an effective adjunct test to newborn audiologic screening, improving time to diagnosis and treatment. Many such panels exist and provide rapid and relatively inexpensive screening of hundreds of common HL genes (e.g., MiamiOtoGenes Panel).2

Syndromic HL is associated with other health issues like eye disease and cardiac anomalies. However, those with non-syndromic HL have no other symptoms and do not need any expensive workup for non-otologic diseases. Knowing the specific genetic cause of HL can save parents unnecessary expense and worry, while helping to guide efficient workup and timely treatment of HL. Similarly, knowing the inheritance pattern allows parents to be informed regarding the risk of hearing impairment in any future children.

A genetic diagnosis can help predict response to cochlear implantation. For example, patients with the GJB2 mutation show an excellent response to cochlear implants, while those with genes affecting the cochlear nerve itself showed worse post-implant performance.3 Knowing this before implantation can help set expectations of post-implant auditory function.

Certain mutations predispose a patient to acquired HL when exposed to various environmental factors. For example, prescribing the antibiotic Streptomycin to a patient with the m.A1555G mutation puts the patient at high risk for HL.4 We can prevent this type of HL by screening for this mutation prior to giving these types of medications. If a patient was screened in advance for this type of mutation, a practitioner prescribing these medications might be alerted by the EHR to warn of the patient's susceptibility to drug-induced HL.

Genetic testing and research open the door to curing some types of HL. With the recent advent of the CRISPR/Cas9 system for genetic manipulation, replacing a single mutation with a functional allele is quickly becoming a reality. Early intervention in genetic HL of progressive onset could effectively prevent the onset of certain types of hearing impairment.5

There remain some challenges to widespread use of genetic testing in audiology. Causative mutations vary widely by population; for example, GJB2 mutations are common among Caucasians, but almost non-existent in populations of African descent.6 Population-based genetic panels must be developed to include the commonly affected HL genes in that population or region. Privacy issues are always a concern with genetic information, raising concerns for potential abuse of genetic information by medical insurers, employers, and others. The expense of genetic testing, while dramatically reduced compared to prior decades, must be justified with corresponding improvements in patient outcomes. Guidelines of which patients to send for genetic testing, which set of genes to test, and when to do so must be developed.7 Finally, improving education of genetic principles and counseling in audiology and otolaryngology training will be of paramount importance as the field of genetic audiology continues to evolve.

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