Expansion of genotype/phenotype correlation in an individual with compound heterozygous variants in CYP51A1 and congenital cataract.

Numerous genetic conditions are represented within the biochemical pathway for de novo cholesterol biosynthesis. Among the emerging disease-gene associations is CYP51A1, encoding a lanosterol demethylase enzyme. Biallelic variants in CYP51A1 have been associated with congenital cataracts and variable liver disease but an appreciation of genotype/phenotype correlation is lacking due to the limited number of patients described. Here we report a 21 month-old female with congenital cataracts harboring compound heterozygous variants of uncertain significance in CYP51A1. Functional studies were performed to resolve the impact of these variants, demonstrating effects at the both the transcript and protein level, and clear evidence of pathogenicity. Molecular analysis of primary lymphoblastoid cells from the proband revealed defects in transcript expression, reduced protein abundance, and a loss of enzymatic function resulting in lanosterol accumulation and increased sensitivity to ferroptosis. These data provide supporting evidence of the association between CYP51A1 defects and congenital cataract that will aid in further establishing a genotype/phenotype correlation.