Two Different Connexin 26 Mutations in an Inbred Kindred Segregating Non-Syndromic Recessive Deafness: Implications for Genetic Studies in Isolated Populations

摘要: Non-syndromic recessive deafness (NSRD) is the most common form of prelingual hereditary hearing loss. To date, 10 autosomal NSRD loci (DFNBs) have been identified by genetic mapping; at least three times as many additional are expected to be identified. We performed linkage analyses in two inter-related inbred kindreds, comprised >50 affecteds, from a single Israeli-Arab village segregating NSRD. Genetic mapping two-point and multi-point analysis candidate regions gene on human chromosome 13q11 (DFNB1). Haplotype analysis, using eight microsatellite markers spanning 15 cM 13q11, suggested segregation different mutations this kindred: affected individuals were homozygotes for either haplotype or compound heterozygotes. The connexin 26 gap junction protein, recently shown mutant both dominant deafness, maps locus. distinct mutations, W77R Gdel35, which likely inactivate 26. Gdel35 change occurs mutational hotspot within gene. recombination marker alleles polymorphisms studied known map distances allowed us estimate age 3-5 generations (75-125 years). This study independently confirms identity an Importantly, we demonstrate that small populations with high rates consanguinity, compared large outbred populations, may very recent origin show allelic diversity.