Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss

Mutations in the human gap junction beta -2 gene (GJB2) that encodes connex in-26 have been shown to cause non-syndromic sensorineural hearing loss (NS SNHL) at the DFNB1 locus on 13q11. Functional and genetic data regarding th e disease causing potential of one particular GJB2 sequence variant, 101 T- ->C (M34T), have proven contradictory. In this study, we found the prevalen ce of the M34T allele in a cohort of white sib pairs and sporadic cases wit h NSSNHL from the United Kingdom and Ireland to be 3.179% of chromosomes sc reened. Significantly, we identified the first M34T/M34T genotype cosegrega ting in a single family with mid to high frequency NSSNHL. Screening a cont rol population of 630 subjects we identified 25 M34T heterozygotes; however , no M34T homozygotes were detected. Surprisingly, the majority of M34T all eles (88%) were in cis with a 10 bp deletion in the 5' non-coding sequence. This non-coding deletion was also homozygous in the homozygous M34T subjec ts. Microsatellite analysis of flanking loci in M34T heterozygotes and cont rols does not define an extensive ancestral haplotype but preliminary data suggest two common alleles in subjects with the M34T allele. In summary, we provide data that support M34T acting as a recessive GJB2 allele associate d with mild-moderate prelingual hearing impairment.