GJB2 mutations and degree of hearing loss: a multicenter study

Abstract

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

Figure 1

Relative frequencies of the degree of HI in the three classes of genotypes. The actual number of participants is given in parentheses. The three classes were biallelic truncating (T/T), compound heterozygous truncating/nontruncating (T/NT), and biallelic nontruncating (NT/NT). There were significant differences among the three classes, with χ² testing (P<.0001). An additional distinction between 35delG and non-35delG mutations in the T/T and T/NT classes was made, but statistical analysis (χ² test) revealed no significance among these subgroups (data not shown). The number of persons is shown under each subgroup.

Figure 2

Scatter diagrams of the PTA_0.5,1,2kHz of groups with specific genotypes. The genotypes were divided into three classes, truncating/truncating (A), truncating/nontruncating (B), and nontruncating/nontruncating (C). The genotypes are shown (left to right) in descending order of group median PTA_0.5,1,2kHz. The dividing lines used to dichotomize the threshold data in any group, as well as the reference group (“ref”), are shown as horizontal lines at 100 dB (∼P50 of the reference group), 85 dB (∼P25), and 55 dB (∼P5). The P value indicated above the panel frame relates to the Fisher’s exact test applying this dichotomy to both the reference group and the test group. HL=hearing loss; “del(GJB6)” represents the del(GJB6-D13S1830 mutation.

Figure 2

Scatter diagrams of the PTA_0.5,1,2kHz of groups with specific genotypes. The genotypes were divided into three classes, truncating/truncating (A), truncating/nontruncating (B), and nontruncating/nontruncating (C). The genotypes are shown (left to right) in descending order of group median PTA_0.5,1,2kHz. The dividing lines used to dichotomize the threshold data in any group, as well as the reference group (“ref”), are shown as horizontal lines at 100 dB (∼P50 of the reference group), 85 dB (∼P25), and 55 dB (∼P5). The P value indicated above the panel frame relates to the Fisher’s exact test applying this dichotomy to both the reference group and the test group. HL=hearing loss; “del(GJB6)” represents the del(GJB6-D13S1830 mutation.

Figure 2

Scatter diagrams of the PTA_0.5,1,2kHz of groups with specific genotypes. The genotypes were divided into three classes, truncating/truncating (A), truncating/nontruncating (B), and nontruncating/nontruncating (C). The genotypes are shown (left to right) in descending order of group median PTA_0.5,1,2kHz. The dividing lines used to dichotomize the threshold data in any group, as well as the reference group (“ref”), are shown as horizontal lines at 100 dB (∼P50 of the reference group), 85 dB (∼P25), and 55 dB (∼P5). The P value indicated above the panel frame relates to the Fisher’s exact test applying this dichotomy to both the reference group and the test group. HL=hearing loss; “del(GJB6)” represents the del(GJB6-D13S1830 mutation.

Figure 3

Audiogram format for genotypes with an HI that was significantly different from that of the reference group of 35delG homozygotes. Only genotypes represented by a minimum of five persons and with an SD <25 dB are included. Median (P50) threshold (solid line) and P10 and P90 thresholds (dashed lines) are shown only for n>10. The reference group (“Ref”) is included and is shaded in gray. “del(GJB6)” represents the del(GJB6-D13S1830 mutation.