MUTATIONS IN THE CONNEXIN 26 GENE (GJB2) AMONG ASHKENAZI JEWS WITH NONSYNDROMIC RECESSIVE DEAFNESS

Background Mutations in the GJB2 gene cause one form of nonsyndromic r ecessive deafness. Among Mediterranean Europeans, more than 80 percent of cases of nonsyndromic recessive deafness result from inheritance o f the 30delG mutant allele of GJB2. We assessed the contribution of mu tations in GJB2 to the prevalence of the condition among Ashkenazi Jew s. Methods We tested for mutations in GJB2 in DNA samples from three A shkenazi Jewish families with nonsyndromic recessive deafness, from As hkenazi Jewish persons seeking carrier testing for other conditions, a nd from members of other ethnic groups. The hearing of persons who wer e heterozygous for mutations in GJB2 was assessed by means of pure-ton e audiometry, measurement of middle-ear immittance, and recording of o toacoustic emissions. Results Two frame-shift mutations in GJB2, 167de lT and 30delG, were observed in the families with nonsyndromic recessi ve deafness. In the Ashkenazi Jewish population the prevalence of hete rozygosity for 167delT, which is rare in the general population, was 4 .03 percent (95 percent confidence interval, 2.5 to 6.0 percent), and for 30delG the prevalence was 0.73 percent (95 percent confidence inte rval, 0.2 to 1.8 percent). Genetic-linkage analysis showed conservatio n of the haplotype for 167delT but the existence of several haplotypes for 30delG. Audiologic examination of carriers of the mutant alleles who had normal hearing revealed subtle differences in their otoacousti c emissions, suggesting that the expression of mutations in GJB2 may b e semidominant. Conclusions The high frequency of carriers of mutation s in GJB2(4.76 percent) predicts a prevalence of 1 deaf person among 1 765 people, which may account for the majority of cases of nonsyndromi c recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggests that this alle le has a single origin, whereas the multiple haplotypes with the 30del G mutation suggest that this site is a hot spot for recurrent mutation s. (N Engl J Med 1998;339:1500-5.) (C) 1998, Massachusetts Medical Soc iety.