Homozygosity for the V37I GJB2 mutation in fifteen probands with mild to moderate sensorineural hearing impairment: further confirmation of pathogenicity and haplotype analysis in Asian populations

Abstract

Hearing impairment affects 1 in 650 newborns, making it the most common congenital sensory impairment. Autosomal recessive nonsyndromic sensorineural hearing impairment (ARNSHI) comprises 80% of familial hearing impairment cases. Mutations in GJB2 account for a significant number of ARNSHI (and up to 50% of documented recessive (e.g., more than 1 affected sibling) hearing impairment in some populations). Mutations in the GJB2 gene are amongst the most common causes of hearing impairment in populations of various ethnic backgrounds. Two mutations of this gene, 35delG and 167delT, account for the majority of reported mutations in Caucasian populations, especially those of Mediterranean and Ashkenazi Jewish background. The 235delC mutation is most prevalent in East Asian populations. Some mutations are of less well-characterized significance. The V37I missense mutation, common in Asian populations, was initially described as a polymorphism and later as a potentially pathogenic mutation. We report here on 15 unrelated individuals with ARNSHI and homozygosity for the V37I GJB2 missense mutation. Nine individuals are of Chinese ancestry, two are of unspecified Asian descent, one is of Japanese descent, one individual is of Vietnamese ancestry, one of Philippine background and one of Italian and Cuban/Caucasian background. Homozygosity for the V37I GJB2 mutation may be a more common pathogenic missense mutation in Asian populations, resulting in mild to moderate sensorineural hearing impairment. We report a presumed haplotype block specific to East Asian individuals with the V37I mutation encompassing the GJB2 gene that may account for the high prevalence in East Asian populations.

Keywords: China; GJB2; V37I; haplotype; hearing impairment.

FIG. 1

200 MB region at GJB2-GJB6 locus showing high linkage disequilibrium. Positions of the 13 SNPs comprising the proposed haplotype are shown in relation to the V37I mutation. Reference allele and the allele represented in Asian V37I probands at each SNP are shown. SNP1 = rs9578257 (15,253 bp downstream from V37I mutation), SNP2 = rs2313475 (12,834 bp downstream), SNP3 = rs3751385 (654 bp downstream ), SNP4 = rs870729 (18,269 bp upstream), SNP5 = rs11620460 (18,549 bp upstream), SNP6 = rs1889784 (18,622 bp), SNP7 = rs6490527 (20,819 bp), SNP8 = rs7981756 (27,132 bp), SNP9 = rs7330206 (28,574 bp), SNP10 = rs2065796 (30,259 bp), SNP11 = rs945369 (37,663 bp), SNP12 = rs7328044 (48,953 bp), SNP13 = rs945373 (50,949 bp). SNP14 (rs9509119; 60,433 bp upstream) is included to determine the age of the mutation. (elements for this figure were adapted from the UCSC Genome Browser: http://genome.ucsc.edu/)