Molecular diagnosis of autosomal dominant and autosomal recessive congenital cataract families from North India

Abstract

Abstract Background To investigate the underlying genetic defects in two autosomal dominant (ADCC) and an autosomal recessive (ARCC) congenital cataract families from North India. Methods Detailed family history was collected, and pedigrees drawn followed by slit-lamp examination and lens photography. Mutation screening performed using Sanger sequencing in the known candidate genes for crystallins, connexins, and membrane proteins. Various bioinformatics tools were used to assess the pathogenicity of the identified variants. Results In two ADCC families with posterior lenticonus cataract, a novel change (c.263C > T; p.P88L) in GJA3 (CC-281 family) and a previously reported substitution (c.388C > T; p.R130C) in LIM2 in second ADCC family (CC-3015) was observed. In an ARCC family (CC-3005) having bilateral central pulverulent cataract, a novel frameshift deletion c.764delT; p.L255R46fs) in GJA3 was detected. The observed variants segregated completely with the phenotypes in the affected members and were neither present in unaffected family members nor in the ethnically matched 150 controls, hence excluding these as polymorphisms. Conclusions Present study identified two novel mutations i.e., c.263C > T (p.P88L) and c.764delT (p.L255R46fs) in GJA3 in an ADCC and an ARCC family having posterior lenticonus and central pulverulent cataract, respectively. In second ADCC family with posterior lenticonus cataract, a previously reported mutation c.388C > T (p.R130C) in LIM2 was observed. This indicates R130 a mutation hotspot as previously two ADCC families one each of European and Chinese descent also harbored the same substitution, however, with different phenotypes i.e., pulverulent and nuclear cataracts. Findings in the present study thus expand the mutation spectrum and phenotypic heterogeneity linked with GJA3 and LIM2.