Genomic Approaches to Diagnosis in Congenital and Developmental Cataract: Comparison of Panel Versus Whole Genome Sequencing, Diagnostic Yield, Variant Spectrum, Genotype-Phenotype Correlations, and Implications for Counseling.

Abstract

Congenital cataracts are a leading cause of childhood blindness, with clinical impact due both to visual impairment and associated systemic disorders. They exhibit clinical and genetic heterogeneity, with pathogenic variants identified in more than 100 genes complicating genotype-phenotype correlation. Accurate molecular diagnosis is essential for prognosis, reproductive counseling, and tailored surveillance and management. Whole genome sequencing (WGS) offers advantages over gene panels by detecting a broader spectrum of variants, including copy number changes, structural rearrangements, cryptic variants, and those in repetitive regions, thereby improving diagnostic yield, especially when interpreted through multidisciplinary team meetings (MDTMs). A retrospective review was performed of 119 consecutive patients undergoing genetic testing for congenital cataracts in the North Thames Genomic Laboratory Hub. Genetic analysis was performed using either targeted gene panels in 76 probands (64%) (2016-2021) or WGS in 43 (36%) (2021-2025). Clinical data were extracted to classify cases as syndromic or nonsyndromic and assess diagnostic outcomes, with complex cases discussed at MDTMs. Nonsyndromic (isolated or wider ocular) and syndromic cataracts accounted for 52.1% and 47.8% of cases, respectively, consistent with previous literature describing frequent multisystem involvement. WGS increased diagnostic yield by 10% compared with gene panels, primarily through detection of variants missed by panel-based approaches. Overall molecular diagnosis was 42%, with higher rates achieved in nonsyndromic forms (51.6%). WGS appears more effective for establishing a diagnosis in congenital cataracts than gene panels, because of its ability to detect diverse pathogenic variants. This is critical for provision of prognosis, reproductive counseling, and further management, especially given the high rate of associated syndromic conditions. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.