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

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

Automated summary

Variants in the GJA3 and GJA8 genes are common causes of inherited pediatric cataract, accounting for up to 18% of cases. However, many of these variants lack sufficient evidence of pathogenicity, highlighting the need for standardized functional data to evaluate their specific effects on protein function.