GJB2: the spectrum of deafness-causing allele variants and their phenotype

Abstract

Genetic testing was completed on 1,294 persons with deafness referred to the Molecular Otolaryngology Research Laboratories to establish a diagnosis of DFNB1. Exon 2 of GJB2 was screened for coding sequence allele variants by denaturing high-performance liquid chromatography (DHPLC) complemented by bidirectional sequencing. If two deafness-causing mutations of GJB2 (encoding Connexin 26) were identified, further screening was not performed. If only a single deafness-causing mutation was identified, we screened for the g.1777179_2085947del (hereafter called del(GJB6-D13S1830); GenBank NT_024524.13) and mutations in the noncoding region of GJB2. Phenotype-genotype correlations were evaluated by categorizing mutations as either protein truncating or nontruncating. A total of 205 persons carried two GJB2 exon 2 mutations and were diagnosed as having DFNB1; 100 persons carried only a single deafness-causing allele variant of exon 2. A total of 37 of these persons were c.35delG carriers, and 51 carried other allele variants of GJB2. Persons diagnosed with DFNB1 segregating two truncating/nonsense mutations had a more severe phenotype than persons carrying two missense mutations, with mean hearing impairments being 88 and 37%, respectively (P < 0.05). The number of deaf c.35delG carriers was greater than expected when compared to the c.35delG carrier frequency in normal-hearing controls (P < 0.05), suggesting the existence of at least one other mutation outside the GJB2 coding region that does not complement GJB2 deafness-causing allele variants.

Figure 1.

Genotype-phenotype correlations for biallelic GJB2 mutation carriers show that percent hearing impairment is highest in persons who are [c.35delG]+[c.35delG] homozygotes and lowest in persons who carry two missense mutations of GJB2 (P<0.05; Fisher exact test). In persons who are compound heterozygotes and carry a single c.35delG allele, severe-to-profound deafness is more common than in persons who carry two missense mutations of GJB2 (P<0.05; Fisher exact test) (A, [c.35delG]+[c.35delG] homozygotes; B, [c.35delG]+[non-c.35delG] compound heterozygotes; C, biallelic missense mutations of GJB2).