< Program

Technology Update Session

Session 2C
Important Considerations for Audiologists in the Diagnosis and Understanding of Genetic Hearing Loss
Michelle D. Valero, PhD, Akouos, A Wholly Owned Subsidiary of Eli Lilly and Company 

In many cases, the cause of early-onset hearing loss is an underlying genetic condition; genetic testing is recommended by relevant clinical guidelines as best medical practice. A genetic diagnosis may help inform medical management and decision-making by providing useful information about likelihood of a syndromic condition, whether hearing loss is expected to be stable or progressive, the inheritance risk, and the prospect of benefit of clinical interventions. Otoferlin gene (OTOF)-mediated hearing loss is a non-syndromic form of genetic, congenital sensorineural hearing loss caused by mutations in OTOF, the gene that encodes the otoferlin protein. OTOF-mediated hearing loss initially presents as a form of auditory neuropathy, in which auditory brainstem responses (ABRs) are abnormal or absent and otoacoustic emissions (OAEs) and/or cochlear microphonics are present. There are several challenges in the diagnosis of OTOF-mediated hearing loss. Infants who are screened by OAEs alone can pass newborn hearing screening despite having functionally profound hearing loss, whereas ABR or combined ABR and OAE screening would identify the hearing deficit associated with an auditory neuropathy phenotype. In addition, OAEs decline with age in individuals with OTOF-mediated hearing loss. Based on a comprehensive literature review of 130 peer-reviewed articles with genetic and audiologic data for 408 individuals, OAEs can be absent within the first few years of life, and the likelihood of identifying individuals with present OAEs substantially decreases within the first decade.There are approximately 125 known different genes that lead to various forms of non-syndromic hearing loss, many of which are very rare. Developing potential clinical interventions for rare conditions requires a comprehensive understanding of how the condition typically presents (e.g., common symptoms, typical test results, etc.), how the condition might progress over time, and who is typically affected by the condition. For rare conditions, natural history studies are often conducted; these are observational studies intended to track the course of a condition over time. Results from natural history studies and other types of natural history research can inform the clinical trial design for a therapeutic candidate, including eligibility criteria, outcomes, and safety measures. A natural history study of OTOF-mediated hearing loss is being conducted to identify any demographic, genetic, or other variables that may correlate with the condition's clinical presentation and outcomes. Several gene therapy clinical trials for inner ear disorders are ongoing, and genotype is a critical eligibility criterion. Increasing awareness of genetic testing options for potentially eligible individuals will better enable families to consider all potential treatment options.


Michelle Valero received her PhD in Neurobiology from the University of Texas in San Antonio and then trained with Dr. Charles Liberman as a postdoctoral fellow at Massachusetts Eye and Ear. As Senior Director and Head of the Early Preclinical Development Team at Akouos, she now leads a diverse team of nonclinical scientists responsible for testing the efficacy and safety of product candidates from early discovery through IND-enabling studies.