Genetic analysis and clinical characteristics of sporadic and familial congenital cataracts in southern Chinese families.

INTRODUCTION

Congenital cataract is a major cause of blindness and severe visual impairment in children. It may occur as an isolated ocular abnormality or in combination with microcornea, microphthalmia, aniridia, or glaucoma. It can also be part of syndromic conditions. Whole-exome sequencing (WES) is now recognized as an appropriate first-line approach for genetic testing in patients with congenital cataract. In this study, we use WES to characterize the genotype spectrum in a pediatric cataract cohort from southern China.

METHODS

In this study, we aimed to clarify the genetic basis of congenital cataract in 40 families from southern China by WES. All candidate variants were confirmed by Sanger sequencing. After bioinformatic analysis, we prioritized rare or novel variants predicted to have moderate to damaging effects and assessed their segregation within each family.

RESULTS

In this cohort of 40 probands with congenital cataract, pathogenic/likely pathogenic variants were identified in 15 (37.5%) individuals, including 6 sporadic cases and 9 familial cases. The identified variants involved 12 genes (CRYBB3, CRYBB2, CRYGS, CRYAA, GJA8, MIP, NHS, BCOR, COL11A1, PAX6, FTL, and FYCO1). In total, 15 pathogenic/likely pathogenic variants were detected, of which 7 were novel. Among genotype-positive patients, seven presented with syndromic cataract, whereas eight had non-syndromic cataract.

DISCUSSION: This study performed WES in 40 probands with congenital cataracts from southern China and achieved a molecular diagnostic yield of 37.5%. Pathogenic/likely pathogenic variants were predominantly identified in crystallin genes, genes encoding lens membrane proteins, and genes implicated in syndromic forms of disease. Notably, a substantial proportion of apparently sporadic cases harbored variants suggestive of a de novo origin. These findings support the clinical utility of WES in clarifying the genetic basis of genetically heterogeneous congenital cataract. They also underscore the limitations of WES compared with whole-genome sequencing (WGS) and highlight the need for larger cohorts and functional validation of candidate variants.