Structural eye disease

Gene: FOXE3

Comment on mode of inheritance: MOI should be updated from ' BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' at the next GMS panel update.

As highlighted in review by Dorine Bax, at least 6 cases with heterozygous variants and cataracts and/or anterior segment dysgenesis have been reported, which appear to represent a spectrum of disease rather than separate disease entities. Both presentations are relevant to this panel and therefore should be included. AD inheritance is discussed in ClinGen and OMIM curations of this gene-disease association. Cases with AR inheritance generally have more severe presentation.

Created: 30 Jul 2025, 9:30 a.m. | Last Modified: 30 Jul 2025, 9:30 a.m.

Panel Version: 4.17

Green List (high evidence)

There are many reports reporting biallelic FOXE3 variants in families with anterior segment anomalies and/or microphthalmia, warranting a recessive inheritance label. However, heterozygous variants causing a c-terminal extension of the protein have been reported in 6 unrelated families with congenital cataract and/or structural eye conditions (PMID: 21150893 (Doucette et al. 2011), PMID: 19708017 (Iseri et al. 2009), PMID: 20806047 (Bremond-Gignac et al. 2010), PMID: 11159941 (Semina et al. 2001), PMID: 34046667 (Reis et al. 2021, 2 families), these are neatly summarised by one of the reviewers. Although the family described by PMID: 20806047 and PMID: 11159941 only have congenital cataract, the four remaining families all have members with conditions that fall within the anterior segment dysgenesis spectrum, and as such a dominant mode of inheritance should be included.

Created: 17 Jan 2025, 3:40 p.m. | Last Modified: 17 Jan 2025, 3:40 p.m.

Panel Version: 4.1

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
HP:0007700; HP:0000568; HP:0007707; HP:0000589; HP:0000519

Publications

• PMID: 21150893
• 9708017
• 34046667

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Leaving mode of inheritance as biallelic for now. 2 monoallelic cases with coloboma, or both coloboma and microphthalmia so flagged with MOI_watchlist tag.

Created: 10 Nov 2021, 4:59 p.m. | Last Modified: 10 Nov 2021, 4:59 p.m.

Panel Version: 1.91

Review of mode of inheritance:

There are many reported cases of biallelic variants in FOXE3 associated with an eye phenotype, particularly cataracts, aphakia, microphthalmia and sclerocornea (PMID: 27218149 Khan et al 2016, PMID: 16826526 Valleix et al 2006, PMID: 19708017 Iseri et al 2009, PMID: 20140963 Reis et al 2010, PMID: 20664696 Ali et al 2010, PMID: 20361012 Anjum et al 2010, PMID: 24019743 Pantoja-Melendez et al 2013, PMID: 27669367 Saboo et al 2017, PMID: 29878917 Quiroz-Casian et al 2018, PMID: 32436650 Taha Najim et al 2020, PMID: 34046667 Reis et al 2021). Glaucoma is also noted in some individuals. Heterozygous carriers are largely unaffected in these cases.

Patients with monoallelic variants in FOXE3 and an eye phenotype are also reported, but only 2 patients show coloboma, or both coloboma and microphthalmia (both reported in Iseri et al 2009).

PMID: 11159941 - Semina et al 2001 - screened FOXE3 in a cohort of 161 unrelated individuals affected with anterior segment ocular disorders and identified a 1 bp insertion in FOXE3 in a proband and affected mother that was not found in controls. Both affected individuals had prominent anterior Schwalbe’s line (posterior embryotoxon) and cataracts.

PMID: 19708017 - Iseri et al 2009 - identified 2 pedigrees with dominant mutations in the FOXE3 gene by screening a large cohort of 236 anophthalmia-microphthalmia subjects; one with anterior segment anomalies, including Peters’ anomaly, early onset cataract, and coloboma, and another with microphthalmia, coloboma, and cerulean type (blue dot) cataracts.

PMID: 20806047 - Bremond-Ginac et al 2010 - a dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract.

PMID: 21150893 - Doucette et al 2011 - sequenced 9 candidate genes in a large Newfoundland family with 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly and found a c.959G>T) substitution that replaces the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Analysis of lympohocytes suggests the c.959T allele is absent rather than an extended protein being expressed.

PMID: 11980846 - Ormestad et al 2002 - one individual with Peters anomaly (with eccentric corneal opacities and glaucoma but not cataract) was found to be heterozygous for a nonconservative missense mutation in FOXE3. 40% of mice heterozygous for Foxe3(dyl) have corneal and lenticular defects.

PMID: 34046667 - Reis et al 2021 - 2 families reported with dominant pathogenic extension alleles which modify the stop codon but keep the amino acids in frame, adding a 72–amino acid nonsense peptide. Cataracts were found in all cases where the lens could be evaluated. Eye size was normal in all individuals, but mild anterior segment anomalies affecting the cornea and/or iris were noted in some individuals. Sclerocornea was observed in two family members (15C and 16B).

Created: 9 Sep 2021, 10:12 a.m. | Last Modified: 10 Nov 2021, 4:57 p.m.

Panel Version: 1.88

Phenotypes
Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968

Publications

• 27218149
• 16826526
• 19708017
• 20140963
• 20664696
• 20361012
• 24019743
• 27669367
• 29878917
• 32436650
• 34046667
• 11159941
• 19708017
• 20806047
• 21150893
• 11980846
• 34046667

Green List (high evidence)

DB Many families with microphthalmia, and anterior segment disorders published. Heterozygous non-stop variants have been reported

Created: 19 Jun 2019, 3:32 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Anterior segment dysgenesis 2, multiple subtypes 610256; Anterior segment mesenchymal dysgenesis 107250

Publications

• 11159941
• 21150893
• 27218149
• 16826526
• 20361012
• 24859618, 19708017

Mode of pathogenicity
Other - please provide details in the comments

Green List (high evidence)

Submitted on behalf of Professor Nicola Ragge (Wessex and West Midlands GLH). DB Many families with microphthalmia, and anterior segment disorders published. Heterozygous non-stop variants have been reported

Created: 17 Apr 2019, 3:30 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Anterior segment dysgenesis 2, multiple subtypes 610256; Anterior segment mesenchymal dysgenesis 107250

Publications

• 11159941
• 21150893
• 27218149
• 16826526
• 20361012
• 24859618, 19708017

Mode of pathogenicity
Other - please provide details in the comments

Variants in this GENE are reported as part of current diagnostic practice