Molecular epidemiology of Chinese Han deaf patients with bi-allelic and mono-allelic GJB2 mutations

Recessive mutations in GJB2 is the most common cause of genetic hearing loss worldwide. The aim of this study is to determine the spectrum and frequency of GJB2 variants in Chinese Han deaf patients and to investigate the underlying causative genes in patients with mono-allelic GJB2 mutations.

We analyzed the mutation screening results of GJB2 in 1852 Chinese Han probands with apparently autosomal-recessive hearing loss in our laboratory. Targeted next-generation sequencing of 139 known deafness-related genes were performed in 44 probands with mono-allelic GJB2 mutations.

Bi-allelic GJB2 mutations was identified in 25.65% of patients, in which the c.235delC (p.L79Cfs*3) mutation is the most frequent cause for both severe-to-profound (84.93%) and mild-to-moderate hearing loss (54.05%), while the c.109G > A (p.V37I) mutation is another frequent cause for mild-to-moderate hearing loss (40.54%). In 3.89% of patients only one mutant allele can be identified in GJB2. Targeted next generation sequencing in 44 such probands revealed digenic heterozygous mutations in GJB2/GJB6 and GJB2/GJB3 as the likely pathogenic mechanism in three probands. In 13 probands, on the other hand, pathogenic mutations in other deafness-associated genes (STRC, EYA1, MITF, PCDH15, USH2A, MYO15A, CDH23, OTOF, SLC26A4, SMPX, and TIMM8A) can be identified as the independent genetic cause, suggesting that the mono-allelic GJB2 mutations in those probands is likely co-incidental.

Our results demonstrated that GJB2 should be a primary target for mutation screening in Chinese Han deaf patients, and those with mono-allelic GJB2 mutations should be further screened by next generation sequencing.