Submission Details

The FOXE3 gene was first reported in relation to ocular disease in 2001, in affected members of a family who inherited anterior segment dysgenesis and cataracts in an autosomal dominant fashion (PMID: 11159941). The known spectrum of disease continued to expand with the 2006 identification of FOXE3 variants in cases of congenital primary aphakia, with an autosomal recessive mode of inheritance (PMID: 16826526). FOXE3 variants have since been identified as the basis for both autosomal recessive and autosomal dominant cases of congenital cataract (PMID: 17893665, PMID: 20806047), indicating the potential for a broad range of phenotypic presentations. Cases diagnosed with anterior segment dysgenesis 2 generally exhibit features such as congenital aphakia, aplasia or hypoplasia of the iris, microphthalmia, Peters anomaly, anterior chamber synechiae, corneal opacity, cataract, coloboma, reduced visual acuity, and/or developmental glaucoma. Cases diagnosed as cataract 34 generally present with congenital cataract either in isolation or accompanied by additional ocular features such as microphthalmia and/or corneal opacity. Cases with autosomal recessive inheritance generally have more severe presentation than those with autosomal dominant inheritance. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the phenotypic variability between cases of anterior segment dysgenesis 2 (MIM# 610256, MONDO:0014508) and cataract 34 (MIM# 612968) appears to represent a spectrum of disease rather than separate disease entities. Despite variability in the mode of inheritance across published cases, the molecular mechanism appears to be FOXE3 loss of function, either by two null or hypomorphic alleles or one dominant negative allele. Therefore, cases caused by inherited FOXE3 variants have been lumped into a single disease entity, referred to as FOXE3-related anterior segment dysgenesis, with a semidominant mode of inheritance.

Eleven suspected disease-causing variants were scored as part of this curation (one nonsense, two frameshift, four missense, and four stop-loss), which have been collectively reported in eleven probands in nine publications (PMID: 11159941, PMID: 16826526, PMID: 17893665, PMID: 19708017, PMID: 20140963, PMID: 20806047, PMID: 21150893, PMID: 25504734, PMID: 27218149). Four of the probands scored in this curation harbored a heterozygous stop-loss variant near the 3’ end of the FOXE3 coding region, while the other seven probands harbored biallelic nonsense, frameshift, or missense FOXE3 variants. Missense variants were generally located within the forkhead domain responsible for DNA binding. The mechanism of pathogenicity appears to be loss of FOXE3 function conferred by either monoallelic dominant negative variants or biallelic null and/or hypomorphic variants. Null or hypmorphic variants do not appear to cause disease in the heterozygous state, as the carriers from families with autosomal recessive inheritance are all reportedly unaffected. Two families with segregation evidence contributed to the scoring of the gene-disease relationship (PMID: 17893665). Additional probands and family segregation evidence were available but not necessary to include, as the maximum scoring for these evidence types had already been reached.

This gene-disease association is also supported by biochemical evidence that FOXE3 encodes a transcription factor that coordinates lens development through control of gene expression (PMID: 27218149). Consistent with this finding, in situ hybridization studies in mouse embryos have shown that Foxe3 is specifically expressed in the developing lens (PMID: 10652278). Spontaneous and targeted mouse models of homozygous Foxe3 disruption recapitulate human patient features such as microphakia, microcoria, microphthalmia, cataract, corneal opacity, corneolenticular adhesions (PMID: 10652278, PMID: 16199865). These models also provide additional insight into disease processes at the histological level, including reduced proliferation and enhanced apoptosis of lens epithelial cells (PMID: 10652278) and disrupted expression of key markers of eye development (PMID: 16199865).

In summary, FOXE3 reached a definitive association with FOXE3-related anterior segment dysgenesis. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Glaucoma / Neuro-Opthalmology Gene Curation Expert Panel on July 20th, 2023 (SOP Version 9).