Genetic Determinants of Non-syndromic Hearing Impairment

Congenital hearing impairment (HI) affects 1-2 per 1000 neonates, of which half would be genetic in etiology. Of the genetic cases, 70% would be non-syndromic in nature. To date ~120 non-syndromic (NS) HI loci have been mapped, for which 39 NSHI genes have been identified. For the known NSHI genes, few studies have been conducted to determine the allelic frequencies and spectra of variants across different populations. Due to the lack of knowledge about functional variants and genotype-phenotype correlations, the goal of a comprehensive genetic HI screening program still requires much groundwork. This thesis has the following objectives: (1) To identify novel loci for non-syndromic hearing impairment; (2) To test candidate genes within the genetic intervals of NSHI loci; (3) To detect novel variants in known NSHI genes and determine their potential functionality; (4) To estimate gene-specific prevalence rates among HI individuals; and (5) To correlate genotype with audiometric phenotype. Five novel loci for autosomal recessive NSHI, namely DFNB47, DFNB55, DFNB62, DFNB65 and DFNB68, are decribed. Although ~4 genes per locus have been screened, the functional variants which caused the HI within the families remain elusive. In addition, three NSHI genes, GJB2, TMC1 and TMIE, were studied among mostly consanguineous Pakistani families. Five novel variants were identified for TMC1, while two new TMIE variants were found. These variants were studied for functionality through bioinformatics, while the overall prevalence of functional variants for each gene was estimated in the Pakistani population. Genotype-phenotype correlation was performed for the GJB2 gene in a Dutch patient population, and for a Swiss-German family that segregates the DFNA24 locus.