Congenital glaucoma with anterior segment dysgenesis in individuals with biallelic CPAMD8 variants

Abstract

Purpose: Congenital glaucoma is a significant cause of irreversible blindness. In some instances glaucoma is associated with developmental abnormalities of the ocular anterior segment, which can impair drainage of aqueous humor, leading to an increase in intraocular pressure. Methods: Genome sequencing was performed on a parent-proband congenital glaucoma trio, with exome sequencing of 79 additional individuals with suspected primary congenital glaucoma. Results: We describe a unique ocular anterior segment dysgenesis associated with congenital glaucoma in four individuals from three unrelated families. In each case, disease was associated with compound heterozygous variants in CPAMD8, a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation of key drainage structures and the development of high intraocular pressure and glaucoma. Conclusions:This study reveals a unique genetic cause of childhood glaucoma, and expands the phenotypic spectrum of CPAMD8-associated ocular disease.