NOVEL MUTATIONS IN THE CONNEXIN-26 GENE (GJB2) THAT CAUSE AUTOSOMAL RECESSIVE (DFNB1) HEARING-LOSS

Mutations in the connexin 26 (Cx26) gene (GJB2) are associated with th e type of autosomal recessive nonsyndromic neurosensory deafness known as ''DFNB1.'' Studies indicate that DFNB1 (13q11-12) causes 20% of al l childhood deafness and may have a carrier rate as high as 2.8%. This study describes the analysis of 58 multiplex families each having at least two affected children diagnosed with autosomal recessive nonsynd romic deafness. Twenty of the 58 families were observed to have mutati ons in both alleles of Cx26. Thirty-three of 116 chromosomes contained a 30delG allele, for a frequency of .284. This mutation was observed in 2 of 192 control chromosomes, for an estimated gene frequency of .0 1 +/- .007. The homozygous frequency of the 30delG allele is then esti mated at .0001, or 1/10,000. Given that the frequency of all childhood hearing impairment is 1/1,000 and that half of that is genetic, the s pecific mutation 30delG is responsible for 10% of all childhood hearin g loss and for 20% of all childhood hereditary hearing loss. Six novel mutations were also observed in the affected population. The deletion s detected cause frameshifts that would severely disrupt the protein s tructure. Three novel missense mutations, Val84Met, Val95Met, and Ser1 13Pro, were observed. The missense mutation 101T-->C has been reported to be a dominant allele of DFNA3, a dominant nonsyndromic hearing los s. Data further supporting the finding that this mutation does not cau se dominant hearing loss are presented. This allele was found in a rec essive family segregating independently from the hearing-loss phenotyp e and in 3 of 192 control chromosomes. These results indicate that 101 T-->C is not sufficient to cause hearing loss.