Localization of Nonsyndromic Hearing Impairment Genes

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PROJECT SUMMARY Hearing impairment (HI) is the most common sensory deficit in the world. Congenital HI occurs in 1-2 per 1000 newborns. Understanding the mechanism of hearing will greatly aid in the development of treatment strategies for HI. Additionally identification of pathogenic variants involved in HI is highly beneficial for genetic screening so that HI can be diagnosed early and intervention can occur at a young age to maximize the child's cognitive, social-emotional, speech and language development. The first step is to map and identify genes involved in the etiology of nonsyndromic (NS) HI. Although ~160 loci for NSHI have been mapped and 90 genes identified, the vast majority of NSHI genes have neither been localized nor identified. The extreme genetic heterogeneity of NSHI is due to the different processes, which can malfunction within the inner ear and cause the HI phenotype. Identification of genes involved in HI is the first step in improving knowledge of the auditory process, which in turn will aid in the development of diagnostic modalities and therapeutic interventions. In order to identify new NSHI genes pedigrees segregating NSHI are being ascertained from Pakistan and Hungary (Roma). The Pakistani pedigrees are usually consanguineous and large. Before gene identification the NSHI gene segregating in a family must be mapped to a genomic region using genotyping and linkage analysis. Therefore, DNA samples from the ascertained pedigrees will undergo whole genome genotyping using the Illumina Infinium HumanCore BeadChip which includes ~282,000 marker loci. Using the generated genotypes linkage and haplotype analysis, and for consanguineous ARNSHI families homozygosity mapping, will be performed to localize NSHI loci to the smallest possible genetic intervals. Multiple families with linkage to the same genetic region will be highly beneficial since these families are likely to have variants within the same gene and will demonstrate that an identified gene is likely to be involved in the etiology of NSHI. The study will provide a rich resource of families to carry out NSHI gene identification using exome and whole genome next-generation sequencing.