Genetic architecture of congenital cataracts: correlation of pathogenic variants with morphology and clinical outcomes

Congenital cataract (CC) refers to lens opacity presented at birth, posing considerable challenges to early childhood visual development and lifelong visual impairment. Although a substantial proportion of CC cases arise from genetic defects, significant gaps remain in the understanding of the genotype-phenotype correlations and the characteristics of potentially pathogenic variants associated with this condition. In the current study, the genetic architecture of CC was investigated by a comparative literature review of 39 known CC-associated genes from Cat-map and HGMD, within an in-house cohort of 150 CC families, complemented by comparing with in-house exome sequencing data from 10,530 families with various eye conditions as well as data from the gnomAD database. Comparative analysis revealed: 1) The in-house genetic diagnostic yield was 63.3% (95/150); 2) Variants in specific genes were correlated with distinct phenotypes, especially for variants in BFSP2, MIP, GJA3, PITX3 and CRYGD; 3) GJA3 variants were often associated with high myopia, and CRYGC variants were often linked to microcornea or microphthalmia; 4) A predominance of CRYAA, LIM2 and MIP variants involve arginine to cysteine changes, and CRYGD variants involve proline to threonine changes; 5) The interpretation of variant pathogenicity is a great challenge. Uncertain variants in CC are present in up to 56.0% of the general population. In conclusion, identified monogenic variants contribute to approximately two-thirds of CC, which has been underestimated as one-third before. These findings broaden the current understanding of the genotype-phenotype relationships in CC and underscore the importance of precise genetic classification for effective diagnosis and management. Further exploration of these genetic factors may provide new insights into prevention and treatment strategies for CC.