Genetic causes of congenital cataract in consanguineous pedigrees from Pakistan

Abstract

Purpose : Congenital cataracts (CCat) are a major cause of vision impairment in children worldwide, and are caused by mutations in more than 50 genes. The purpose of this study was to identify the genetic causes of CCat in three Pakistani families.

Methods : Three unrelated consanguineous pedigrees (F1, F2 and F3), were recruited from the Punjab region of Pakistan and were genetically studied at the Institute of Molecular and Clinical Ophthalmology Basel by whole-exome sequencing and Sanger sequencing. Clinical examination of probands was performed by standard procedures.

Results : Patients from F1 and F2 families had non-syndromic bilateral cataracts whereas patients from F3 family had CCat with microcytic hypochromic anaemia, B-cell immunodeficiency, physical developmental delay, muscular dystrophy, and speaking difficulties without intellectual disabilities. Fundus examination of all patients showed normal retina. Genetic analysis of patients from F1 revealed a novel homozygous stop-gain mutation (NM_001318327.1:c.988C>T, p.[Arg330*]) in DNMBP, whereas patients from F2 carried a new missense mutation (NM_000786.4:c.268T>A, p.[Phe90Ile]) homozygously, in the CYP51A1 gene. Finally, patients from F3 were found to have compound heterozygous variants in the TRNT1 gene: the previously unreported nonsense variant (NM_182916.2:c.433C>T, p.[Gln145*]) and the known mutation (NM_182916.2:c.1246A>G, p.[Lys396Glu]). All variants co-segregated with disease in the respective families.

Conclusions : Our findings expand the mutational spectrum of congenital cataracts and provide new information for further functional studies on the molecular mechanisms leading to these conditions.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.