Hearing Impairment with Monoallelic GJB2 Variants: A GJB2 Cause or Non-GJB2 Cause?

Recessive variants in GJB2 are the most common genetic cause of sensorineural hearing impairment. However, in many patients, only one variant in the GJB2 coding region is identified using conventional sequencing strategy (eg, Sanger sequencing), resulting in nonconfirmative diagnosis. Conceivably, there might be other unidentified pathogenic variants in the noncoding region of GJB2 or other deafness-causing genes in these patients. To address this, a next-generation sequencing–based diagnostic panel targeting the entire GJB2 gene and the coding regions of 158 other known deafness-causing genes was designed and applied to 95 patients with nonsyndromic sensorineural hearing impairment (including 81 Han Taiwanese and 14 Mongolian patients) in whom only a single GJB2 variant had been detected using conventional Sanger sequencing. The panel confirmed the genetic diagnosis in 24 patients (25.3%). Twenty-two of them had causative variants in several deafness-causing genes other than GJB2, including MYO15A, MYO7A, TECTA, POU4F3, KCNQ4, SLC26A4, OTOF, MT-RNR1, MITF, WFS1, and USH2A. The other two patients had causative variants in GJB2, including a Taiwanese patient with a mosaic maternal uniparental disomy c.235delC variant (approximately 69% mosaicism) and a Mongolian patient with compound heterozygous c.35dupG and c.35delG variants, which occurred at the same site. This study demonstrates the utility of next-generation sequencing in clarifying the genetic diagnosis of hearing-impaired patients with nonconfirmative GJB2 genotypes on conventional genetic examinations.