Evaluating gap junction variants for a role in pediatric cataract: an overview of the genetic landscape and clinical classification of variants in the <i>GJA3</i> and <i>GJA8</i> genes

Introduction Variants in the two lens-expressed gap junction genes GJA3 and GJA8 are among most common causes of inherited pediatric cataract. These alone account for up to 18% cases, second only crystallin gene family.Areas covered All published cataract-associated variants were reviewed a role Autosomal dominant inheritance was frequently reported, alongside instances reduced penetrance autosomal recessive disease. Variant curation using ACMG-AMP guidelines identified that many do not meet modern standards clinical interpretation pathogenicity. There is broad phenotypic heterogeneity cataract associated with variants. Pathogenic located throughout both proteins an enrichment N-terminal, first transmembrane domains, extracellular loops.Expert opinion Nearly half observed patients lack sufficient evidence pathogenicity form useful opinion. For variants, this may be rectified over time as variant additional but would vastly accelerated by generation well-characterized standardized functional data evaluating specific effect each on protein function.