Genetic causes of hearing loss from the population to the molecular level

University Of Iowa, Iowa City IA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Sensorineural hearing loss (SNHL) is the most prevalent congenital sensory deficit. In over 50% of cases, the cause is genetic. Genetic testing plays an important role in caring for patients with SNHL, as early intervention programs can significantly improve development and quality of life. More than 64 genes have been causally implicated in SNHL without other defects, termed non-syndromic hearing loss (NSHL). Genetic testing currently focuses on testing only a few of these genes and so in many cases, the genetic cause is never determined. This gap in genetic testing is a result of three factors: 1) the relative contribution of these genes to deafness in the United States is not known;2) a large number of 'deafness'genes have not yet been discovered;3) until recently, sequencing technology has been too costly and time-consuming to permit mutation screening of large numbers of genes on a per-person basis. In this study, we propose to address these issues, thereby improving genetic testing for NSHL. In order to address the need for an efficient and comprehensive genetic testing platform for NSHL we are developing a low-cost diagnostic platform in which high-throughput genomic enrichment is paired with next-generation sequencing to interrogate all genes implicated in NSHL in persons with SNHL. In additional to filling a clinical need, this platform will provide epidemiological data on genetic deafness in the USA, which is currently not available. To increase the rate of discovery of new genes important in the biology of hearing and deafness, we will link the diagnostic platform with a gene discovery platform based on protein expression data from hair bundles. In addition, we propose to use functional studies to gain a better understanding of a known deafness gene, TECTA. We will use AudioGene audio profiling to further define genotype-phenotype correlations in DFNA8/12 and determine if this type of deafness is common in the US population. We will clarify, in part, the functional relationship of 1-tectorin with one of its interacting partners, CEACAM16, to improve our understanding of the molecular mechanisms underlying deafness. Completion of the goals of this project will improve the diagnosis for hereditary hearing loss and provide a greater understanding of the genes involved in hearing. PUBLIC HEALTH RELEVANCE: We will develop a comprehensive genetic testing platform using high throughput sequencing technologies to: 1) improve the clinical care of deaf and hard of hearing persons;and, 2) determine the epidemiology of hereditary hearing loss in the United States. We will optimize novel gene discovery using similar technologies, and study in-depth a known deafness-causing gene to provide a better understanding of the molecular mechanisms of deafness and hearing.