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155217 - Evaluating gap junction variants.pdf (2.34 MB)

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

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journal contribution
posted on 2023-05-21, 16:14 authored by Johanna JonesJohanna Jones, Kathryn BurdonKathryn Burdon

Introduction: Variants 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 covered: All 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 opinion: Nearly 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.


National Health & Medical Research Council


Publication title

Expert Review of Ophthalmology






Menzies Institute for Medical Research


Taylor & Francis

Place of publication

United Kingdom

Rights statement

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

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  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

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