A Collaborative Search for New Genes for Non-Syndromic Deafness

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Program Director/Principal Investigator (Last, First, Middle): Project Summary Clinically significant hearing loss is present in at least 1.9 per 1,000 infants at birth and affects nearly half of the population at some time in their lives. Nearly 70% of congenital or prelingual deafness is genetic in origin, and of these up to 93% are monogenic autosomal recessive traits. Some forms of genetic deafness can be recognized by their associated syndromic features, but in most cases, hearing loss is the only finding (NSHL). DNA variants in currently recognized deafness genes are not detected in more than one-third of affected individuals with autosomal recessive NSHL, leaving large number of families without a molecular diagnosis. We established a repository that contains biological samples and clinical data on about three thousand families with NSHL. Of these, over a thousand include at least two affected members and are consistent with autosomal recessive NSHL. The most common forms of NSHL have been excluded in all families; all known deafness genes were excluded in over four hundred families. We will use genome sequencing to identify underlying coding and non-coding variants in families with autosomal recessive NSHL that remain unsolved in our Repository. Availability of a large number of inbred families will facilitate analysis within autozygous regions. To support the role of identified variants in pathophysiology, we will perform functional experiments utilizing in vitro and mouse models. We have successfully applied this strategy to discover novel deafness genes during the previous cycles of this application. Detected variants and associated audio-vestibular phenotypes will be stored in a database that will be accessible by outside researchers. The outcomes of this proposal will be discoveries of novel coding and non-coding variants in genes and pathways involved in the pathophysiology of deafness, foundation of molecular diagnostic tests for etiological diagnosis, counseling, and candidacy for molecular treatments of affected individuals. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page