Clinically significant hearing loss is present in at least 1.9 per 1,000 infants at birth and affecs at least 30% of the population at some time in their lives. More than 60% 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 abnormality (NSHL). While causal mutations have been identified in one of 58 different genes in a subset of patients with autosomal recessive NSHL (ARNSHL), at least 30% of families do not have an identifiable mutation. Moreover, mutation specific audio-vestibular phenotypes remain largely unknown. Through multiple national and international resources we established a repository that contains biological samples and clinical data on 2,060 families with NSHL. Of these, 796 include at least two affected members and are consistent with ARNSHL Parental consanguinity is present in 1,234 families. The most common forms of NSHL have been excluded in all families. After exclusion of mutations in all known deafness genes via a next-generation sequencing gene panel, we will use whole exome or whole genome sequencing and microarrays to identify causative single nucleotide, indel, and copy number variants in novel deafness genes. Availability of a large number of inbred families will facilitate analysis within autozygous region. To support the role of identified changes in pathophysiology, in vitro and in vivo models will be produced. Mouse mutants will be primarily utilized to reveal the underlying pathophysiology, while zebrafish mutants will be used for those genes suitable for pharmacological intervention. We have successfully applied this strategy to discover novel deafness genes during the previous cycle 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 genes/pathways involved in the pathophysiology of deafness, foundation of molecular diagnostic tests for etiological diagnosis and counseling of deaf individuals, and the development of novel interventional strategies.
The goals of the project are to identify novel genetic causes of autosomal recessive non-syndromic deafness in a large repository of families and confirm their causative roles in extensive functional studies. Identified mutations along with their associated audio-vestibular findings will be stored in an online database to facilitate further studies. The outcome of this proposal will expand the scientific knowledge on the genomic basis of deafness, provide better molecular diagnostic tools to the affected families, and identify potential treatment targets for hearing loss.
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