Mutation screening in autosomal dominant congenital cataract families from North India.

Congenital cataract an opacity of the eye lens is present at birth and results in visual impairment during early childhood. If left untreated, it can lead to permanent blindness. Its prevalence is ten times higher in developing countries like India. Thus, we aimed to investigate the underlying genetic defects in three autosomal dominant congenital cataract (ADCC) families from North India. Detailed family histories were collected, pedigrees drawn followed by slit-lamp examination and lens photography. Mutation screening was performed in the candidate genes for crystallins, connexins, and membrane proteins by Sanger sequencing. Pathogenicity of novel variant was assessed bioinformatically. In an ADCC (CC-3006) family with bilateral membranous cataract and microcornea, a novel change (c.1114C>T;p.P372S) in GJA3 has been detected. In other two ADCC families affected with subcapsular (CC-286) and shrunken membranous hypermature cataract (CC-3014), a nonsense mutation (c.463C>T;p.Q155X) in CRYβB2 and a frameshift deletion (c.590_591delAG;p.E197VfsX22) in CRYβA1/A3 respectively, are observed. These variants segregated completely with the phenotypes in respective families and were absent in their unaffected family members and unrelated controls (tested for novel variant in GJA3). Earlier p.Q155X (CRYβB2) and p.E197VfsX22 (CRYβA1/A3) are reported with entirely different phenotypes. Thus, findings in present study expand the mutation spectrum and phenotypic heterogeneity linked with GJA3, CRYβB2, and CRYβA1/A3 for congenital cataracts. Identifying underlying genetic defects is essential for disease management and appropriate genetic counseling.