Whole-exome sequencing identified a novel missense variant in the connexin 46 (GJA3) gene causing congenital cataract in an Iranian pedigree

Abstract

Abstract Background: Congenital cataract (CC) is the most common reason for visual loss and blindness at birth or early childhood worldwide. The autosomal dominant (AD) inheritance is reported as the most frequent transmission pattern for CC. Connexin 46 (Cx46 coded by GJA3 gene) belongs to the gap junction proteins family which has the main function in the cell communication system of the eye lens. Methods: In the present research, whole-exome sequencing (WES) was done for proband diagnosed by CC, and Co-segregation analysis using Sanger sequencing was performed for the candidate variant on healthy and affected family members. The candidate variant was analyzed with appropriate bioinformatics software and then classified according to the ACMG guideline. Results: WES analysis of proband recognized a novel heterozygous c.146 A>C (p.Q49P) variant in the exon 2 of the GJA3 gene leading to the substitution of a highly conserved Glutamine by Proline at codon 49. The linkage of CC with this variant was observed for three generations in a proband family with AD inheritance. This variant is located on phylogenetically conserved extracellular loop E1 of protein. Extracellular loops play the main role to mediate hemichannel docking between connexons and regulating voltage gating of the channel. Conclusion: Our finding emphasized the role of Cx46 in the pathogenesis of ADCC and the extended mutation spectrum of the GJA3 gene in association with CC.