Research Project
9447279
The goal of this project is to discover and characterize new genes for inherited hearing loss by studying highly informative families from the Middle East. Families from regions with traditions of consanguinity or endogamy have been particularly informative for gene discovery for hearing loss, with other mutations responsible for both recessive and dominant hearing losses subsequently identified in other families. Over the past 19 years, our partnership has discovered seven new genes for hearing loss, contributed to the genotype-phenotype profiles of many others, evaluated the roles of microRNAs in hearing development, and characterized the functions of our mutant genes in patient cells and mouse models. During the current grant period, we published SYNE4 as a new gene for hearing loss and are in the midst of functional studies of five other candidate genes: ATOH1, CDKL3, CTBS, GOSR2, and OTOP2. We have also been at the forefront of application of genomic technologies to hearing research. We were among the first groups to apply exome sequencing to gene discovery for any phenotype and to develop targeted hybridization pools for thorough and efficient screening of candidate deafness genes. Our partnership has complementary strengths at Tel Aviv University, Bethlehem University, and the University of Washington in Seattle. Our greatest asset is our relationship with hundreds of highly informative Palestinian and Israeli families, each with multiple relatives with hearing loss who have been evaluated by audiology and for syndromic features. Complete families participate, are willing to be re-contacted, and remain in touch with us indefinitely. In Aim 1, we will enroll each year all informative members of 80-100 multiplex Palestinian and Israeli families (400-500 individuals) with hearing loss, and use our targeted gene panel to sequence for mutations in known genes for hearing loss. In Aim 2, families not resolved by Aim 1 will be evaluated by whole genome sequencing. Variants prioritized for functional studies will be rare coding sequence variants of predicted damaging effect in new candidate genes that co-segregate with hearing loss; and rare non-coding variants that lie in potential regulatory regions, as defined by several parameters, and that co-segregate with hearing loss. In Aim 3, we will undertake functional studies of these new candidate genes and mutations. Our approaches will include functional analysis of wild type and mutant proteins in transfected cells and cochlear explants, and generation of mouse models of mutations from human families by CRISPR/Cas9 genome editing, followed by characterization of their hearing and inner ear phenotypes. In summary, we propose to use modern tools of genetics and genomics to reveal and characterize genes essential for development and maintenance of hearing. Our discoveries will aid in the development of biological strategies for treatment or cures for deafness.
