2 DIFFERENT CONNEXIN 26 MUTATIONS IN AN INBRED KINDRED SEGREGATING NON-SYNDROMIC RECESSIVE DEAFNESS - IMPLICATIONS FOR GENETIC-STUDIES IN ISOLATED POPULATIONS

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