GENETIC LANDSCAPE OF PRIMARY CONGENITAL GLAUCOMA: FROM LOCUS HETEROGENEITY TO OLIGOGENIC MODELS

Abstract

Primary congenital glaucoma (PCG) is the leading inherited cause of childhood blindness and has long served as a paradigm for monogenic eye disease. Biallelic loss-of-function variants in CYP1B1 at the GLC3A locus remain the single most consistent cause; their contribution, however, ranges from under a quarter of cases in East Asian cohorts to nearly all cases in founder populations such as the Slovak Roma and Saudi Arabian consanguineous families. This review synthesises three decades of linkage, sequencing, and functional data to reassess PCG as a genetic landscape rather than a single Mendelian disease. We revisit the taxonomy of GLC3 loci, including the still largely gene-negative GLC3B and GLC3C intervals and the more recently resolved LTBP2 and TEK genes, and we identify concrete methodological reasons genotype-phenotype correlations diverge between cohorts. Null CYP1B1 alleles reproducibly predict earlier onset and worse surgical outcomes, but penetrance is incomplete and severity varies even within families sharing a genotype, implicating modifier loci such as MYOC, FOXC1, PITX2, and SVEP1. Between 20% and 40% of clinically typical patients remain genetically unsolved after comprehensive screening. We weigh two explanations for this gap – undetected oligogenic interaction versus sequencing-technology limitations – and argue both should be tested empirically before either is favoured. We discuss clinical translation, including tiered sequencing algorithms, interpretation of heterozygous findings, and genetic counselling for sibling risk, and close with concrete priorities: multicentre consortia, functional validation at GLC3B/GLC3C, and near-term as well as long-term strategies for a disease whose therapy must act on development, not degeneration.