Delineation of Novel Autosomal Recessive Mutation in GJA3 and Autosomal Dominant Mutations in GJA8 in Pakistani Congenital Cataract Families

Abstract

Congenital cataract is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic cause of congenital cataract families. DNA samples of a large consanguineous Pakistani family were genotyped with a high resolution single nucleotide polymorphism Illumina microarray. Homozygosity mapping identified a homozygous region of 4.4 Mb encompassing the gene <i>GJA3</i>. Sanger sequence analysis of the <i>GJA3</i> gene revealed a novel homozygous variant c.950dup p.(His318ProfsX8) segregating in an autosomal recessive (AR) manner. The previously known mode of inheritance for <i>GJA3</i> gene mutations in cataract was autosomal dominant (AD) only. The screening of additional probands (<i>n</i> = 41) of cataract families revealed a previously known mutation c.56C>T p.(Thr19Met) in <i>GJA3</i> gene. In addition, sequencing of the exon-intron boundaries of the <i>GJA8</i> gene in 41 cataract probands revealed two additional mutations: a novel c.53C>T p.(Ser18Phe) and a known c.175C>G p.(Pro59Ala) mutation, both co-segregating with the disease phenotype in an AD manner. All these mutations are predicted to be pathogenic by in silico analysis and were absent in the control databases. In conclusion, results of the current study enhance our understanding of the genetic basis of cataract, and identified the involvement of the <i>GJA3</i> in the disease etiology in both AR and AD manners.