Identification and clinical implications of a novel pathogenic variant in the GJB2 gene causes autosomal recessive non-syndromic hearing loss in a consanguineous Iranian family

Mutations in the GJB2 gene, which encodes the connexin26 protein and is involved in inner ear homeostasis, are the most common cause of autosomal recessive non-syndromic hearing loss (ARNSHL) in many populations. This study was aimed to determine the molecular etiology in a consanguineous Iranian family affected by profound ARNSHL. A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 4 affected members. After extraction of genomic DNA, the entire coding region of GJB2 was directly sequenced in all family members. In silico analyses were also performed using available software tools. Sanger sequencing results showed a novel rare homozygous variant (c.109_110insG) in the GJB2 gene. This frameshift variant in exon 2 of the GJB2 gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Confirmation was done with the co-segregation study and checking the frequency of the novel variant in 100 ethnically matched normal control subjects. The present study suggests that investigation of GJB2 mutations may still be useful to determine the etiology of HL in Iran.