A Novel 1259 bp Intragenic Deletion in the GJB2 Gene in a Mexican Family with Congenital Profound Hearing Loss.

Abstract

Hearing loss is a genetically heterogeneous sensory defect for which biallelic pathogenic variants in the GJB2 gene are a frequent cause. Here, we report a novel intragenic large deletion in GJB2 in a Mayan family with several members affected by congenital non-syndromic hearing loss. The analysis of the GJB2 gene in the proband was performed through Sanger sequencing. A novel homozygous 1259 bp deletion in GJB2 was identified, starting at nucleotide 248 of the coding region and ending at nucleotide 825 of the 3'-UTR (g.20188077_20189335del). Bioinformatic tools were used to predict the structural impact of the variant. This deletion would result in a truncated protein of 86 amino acids, p.(Phe83Cysfs*5), disrupting several critical domains of the connexin-26 protein. We developed an endpoint-PCR assay to test for the deletion. It was present homozygously in all affected siblings and was absent in 153 ethnically matched controls with normal hearing. Both parents and two unaffected siblings were heterozygous carriers, consistent with an autosomal recessive inheritance pattern. The identification of this novel large deletion expands the spectrum of GJB2 pathogenic variants causing non-syndromic hearing loss, and it is of concern to GJB2 screening methods that rely primarily on Sanger sequencing for its coding region.