Detection of c.139G>A (D47N) mutation in GJA8 gene in an extended family with inheritance of autosomal dominant zonular cataract without pulverulent opacities by exome sequencing

The aim of this study was to identify the gene causing bilateral autosomal dominant zonular congenital cataract (ADZCC) without pulverulent opacities in an extended Muslim family by exome sequencing and subsequent analysis. An extended family of 37 members (14 affected and 23 unaffected) who belong to different nuclear families was screened for causative gene. Proband and her unaffected son were screened for causative variant by exome sequencing followed by Sanger sequencing of the proband’s entire nuclear family. The rest of the members were further screened for variants detected, by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR). Review of exome sequencing data of the proband and her unaffected son for 40 known genes causing congenital nonsyndromic cataracts revealed two variants, namely c.139G>A (p.Asp47Asn; D47N) in the GJA8 gene and c.2036C>T in the FYCO1 gene to be potentially pathogenic. Further, validation of these two variants in the entire family showed cosegregation of c.139G>A variant in GJA8 with ADZCC without pulverulent opacities. Variation of c.2036C>T in FYCO1 was not associated with disease in the family. The mutation c.139G>A in the GJA8 gene detected in the present study was also previously reported in Caucasian and Chinese families but with different phenotypes, i.e. nuclear and nuclear pulverulent cataracts. Thus, the mutation c.139G>A in GJA8 appears to exhibit marked interfamilial phenotypic variability.