Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10

Abstract

Mutations in the connexin 26 gene (GJB2) are responsible for the major part of nonsyndromic autosomal recessive or apparently sporadic prelingual deafness in Caucasians (DFNB1). We screened 228 German hearing-impaired persons for mutations in the GJB2 gene by sequence analysis. Homozygous or compound heterozygous GJB2 mutations were detected in 38/228 (16.7%) of hearing impaired persons. The most frequently occurring mutation was the c.35delG mutation, which was found in 71.1% of the mutated alleles. The next frequent mutation detected in the group of hearing impaired persons was the c.101T>C mutation (9/76 alleles; 11.8%). One new mutation, c.567delA, was observed. We further studied the presence of a 10bp deletion in the 5' UTR of the GJB2 gene (c.-493del10) which was assumed to occur together with the c.101T>C mutation. Ten out of thirteen patients (76.9%) were found to be carriers of both the c.101T>C mutation and the 10bp variant and in 7/14 alleles a linkage disequilibrium between c.101T>C and the 10bp deletion was proven. In 4/14 alleles the linkage was ruled out and for the remaining 3 cases the phase determination was not possible. Seventy one controls were screened for the prevalence of Cx26 mutations and for the c.-493del10 variant. Heterozygosity frequency in the control group was for c.35delG 4.2%, for c.101T>C 1.4% and for c.-493del10 it was 5.6%.

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

“…12,11,18,10,23,13,24 However, as Griffith et al 10 we reported here five normal hearing subjects carrying a compound heterozygous mutation in which the M34T substitution is associated in trans with a truncated mutation : the 35delG GJB2 mutation or the (GJB6-D13S1830)del. 20 These results indicate that M34T is not a recessive mutation responsible for hearing loss.…”

“…Two recent reports have found a 10 base pairs deletion in the 5 0 UTR of GJB2 that occurs together with the M34T mutation. 11,24 The last one 24 have demonstrated a linkage desequilibrum between these two variants. However, in several families reported in these two studies, 11,24 neither the M34T nor the À493del10 segregated with the deafness.…”

“…The presence of deaf patients homozygous for the M34T variant, as in our report (family no. 7) and in others, 11,24 should not be considered as an argument for the pathogenicity of this variant because if M34T is a frequent polymorphism, it could be fortuitously present in a homozygous state in some patients.…”

Identification and genotype/phenotype correlation of mutations in a large German cohort with hearing loss

“…Moreover, comparison with other studies and their mutation detection rates is difficult with variability of study design, demographic influences and extent of analyzing methods. In relation to other German studies [45][46][47] with an estimated percentage between 6.4 and 16.7 % of patients with biallelic GJB2 mutations our level of 31.3 % is notably higher, leading us to the suggestion that the contribution of GJB2 to nonsyndromic hearing loss is may be a little overrated in German population but still the leading cause for deafness with genetic background.…”

Gap junctions in inherited human disease

“…This study and follow-up studies led to the identification of a homozygous mutation in the GJB2 gene in affected members of three families with autosomal recessive nonsyndromic sensorineural deafness linked to 13q11-q12 [16,64]. Today, more than 90 distinct autosomal recessive mutations of GJB2 are known, including nonsense, missense, splicing, frameshift mutations, and inframe deletions [24, 63,64,166].…”