GJB2 c.235delC variant associated with autosomal recessive nonsyndromic hearing loss and auditory neuropathy spectrum disorder.

Hong Xia,Yong-An Zhou,Zhijian Yang,Hongbo Xu,Jingyan Lv,Lina Gong,Xiangjun Huang,Hao Deng

doi:10.1590/1678-4685-gmb-2017-0318

Abstract

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous neurosensory disorder, usually characterized by congenital or prelingual hearing loss. We report a Han Chinese male, born to consanguineous parents, presenting with nonsyndromic sensorineural hearing loss, whose clinical phenotype was also consistent with auditory neuropathy spectrum disorder (ANSD). After exome sequencing, a gap junction protein beta 2 gene (GJB2) c.235delC variant in the homozygous state was detected in the patient. Both parents were heterozygous for this variant, as documented by Sanger sequencing. The known pathogenic GJB2 c.235delC variant was not detected in 200 healthy controls. It is predicted to be a disease-causing alteration by generating a truncated protein p.(L79Cfs*3), disturbing the appropriate folding and/or oligomerization of connexins and leading to defective gap junction channels. This study shows that the association of homozygosity of the GJB2 c.235delC variant with ARNSHL and ANSD in a patient.

Highlights

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous neurosensory disorder, usually characterized by congenital or prelingual hearing loss, and not accompanied by other clinical features (Xia et al, 2015; Meena and Ayub, 2017)
Since variants in the gap junction protein beta 2 gene (GJB2) were first identified as causative of ARNSHL in 1997 (Kelsell et al, 1997), to date (January, 2019), at least pathogenic variants in other 72 genes have been causally associated with ARNSHL according to the Hereditary Hearing Loss Homepage
The extreme genetic heterogeneity of nonsyndromic hearing loss makes the use of regular Sanger sequencing to identify its genetic cause very challenging, and exome sequencing has been recommended as a cost-effective alternative strategy (Xia et al, 2016)

Summary

Introduction

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous neurosensory disorder, usually characterized by congenital or prelingual hearing loss, and not accompanied by other clinical features (Xia et al, 2015; Meena and Ayub, 2017). Since variants in the gap junction protein beta 2 gene (GJB2) were first identified as causative of ARNSHL in 1997 (Kelsell et al, 1997), to date (January, 2019), at least pathogenic variants in other 72 genes have been causally associated with ARNSHL according to the Hereditary Hearing Loss Homepage (https://hereditaryhearingloss.org). Homozygosity for a GJB2 variant was detected by exome sequencing, as causative of autosomal recessive hearing loss in a Han Chinese male presenting auditory neuropathy spectrum disorder (ANSD).

Results

Conclusion