Biallelic CPAMD8 variants are a frequent cause of childhood and juvenile open-angle glaucoma

Abstract Purpose Developmental abnormalities of the ocular anterior segment can, in some cases, lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective multicenter case series. Participants Two hundred and sixty-eight probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype, and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1, and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment.