Unraveling the genetic architecture of cochleovestibular malformation

SUMMARY Hearing impairment is a common and disabling sensory defect which in a subset of individuals can be due to an abnormal cochleovestibular anatomy. Cochleovestibular (CV) and cochleovestibular nerve (CVN) anomalies can significantly impact a child’s development and currently pose challenges in treatment and management. Little research has been done to understand the etiology of these malformations, especially those that are non- syndromic and severe, such as cochlear aplasia. There is a crucial need to better understand the underlying molecular mechanisms of these conditions to aid in diagnosis, intervention and management. In addition, health disparities exist in the molecular diagnosis and treatment of hearing impairment (HI) in Hispanics, as the molecular etiology of HI has been scarcely studied in this ethnic group. It is imperative to study the etiology of CV/CVN anomalies in diverse racial/ethnic populations to understand which genes/variants are a frequent cause of this disorder in each population. Molecular diagnostics and treatment can therefore be tailored based on population-specific information. We hypothesize that a significant subset of severe non-syndromic CV/CVN anomalies has a genetic etiology, which may differ between populations, and knowledge of this information will improve our understanding of inner ear development. Our preliminary research suggests that rare genetic variants, including de novo variants, are implicated in the development of severe CV/CVN anomalies. Our proposal leverages genomics data and temporal bone imaging data to unravel the molecular basis of non-syndromic CV/CVN malformations. To achieve this, we will 1) recruit and establish a large genomic database of racially/ethnically diverse families with CV/CVN malformations which have been phenotyped in detail. 2) Next, we will determine the genetic spectrum of underlying variation implicated in CV/CVN malformations in both Hispanic and non-Hispanic individuals. 3) Last, using recruited and existing cohorts of individuals with CV/CVN malformations and prelingual sensorineural hearing impairment, we will identify novel causal genes implicated in CV/CVN malformations and assess their expression during early craniofacial and inner ear development. We have assembled a team that has the collective expertise to achieve these aims as well as a prior track record of productive collaboration. This work will elucidate the genetic architecture of severe non-syndromic CV/CVN malformations diverse ethnic/racial populations and improve our basic knowledge of human inner ear development and the mechanisms leading to abnormal development. This knowledge can then be used to improve molecular diagnostics, guide therapeutic intervention and management, predict outcomes, and develop novel therapeutic approaches benefiting individuals of diverse ethnicity/racial background.