FOXE3

Inheritance Pattern: AD

Disease ID:MONDO:0007138

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0005129

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012456

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0044301

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0019625

Submitter: ClinGen

Inheritance Pattern: AD

Disease ID:MONDO:0012456

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0005129

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012456

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Orphanet

Inheritance Pattern: SD

Disease ID:MONDO:0012456

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012456

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0044301

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: ClinGen

*FOXE3* was first reported in relation to autosomal dominant thoracic aortic aneurysm and dissections in 2016 by Kuang *et al* (PMID: 26854927) who described eight heterozygous variants in *FOXE3* suspected to cause disease in individuals with acute aortic dissection inherited in an autosomal dominant manner. In contrast, biallelic variants in *FOXE3* are associated with a spectrum of ocular anomalies such as autosomal recessive anterior segment dysgenesis, congenital cataract, primary aphakia, sclerocornea and microphthalmia (PMIDs: 11159941, 16826526). Per criteria outlined by the ClinGen Lumping and Splitting Work Group, we found differences in molecular mechanisms and inheritance patterns and we did not identify overlap or segregation data in favor of merging these clinical entities. Therefore, familial thoracic aortic aneurysm and dissection (FTAAD), cataract 34 multiple types (MIM# 612968), and anterior segment dysgenesis 2 (also known as congenital primary aphakia) (MIM# 610256) have been split into multiple disease entities. The gene-disease relationships between *FOXE3*, congenital cataract, and anterior segment dysgenesis were curated separately by the ClinGen Glaucoma / Neuro-Opthalmology Gene Curation Expert Panel. This curation is for the gene-disease relationship between *FOXE3* and autosomal dominant familial thoracic aortic aneurysm and aortic dissection (FTAAD) (MONDO:0019625). Evidence supporting this gene-disease relationship between *FOXE3* and FTAAD includes case-level, segregation and experimental data. Four variants (three missense and one frameshift) that have been reported in four probands in two publications (PMIDs: 26854927 and 39226896) are included in this curation. Variants in this gene segregated with disease in 5 additional family members. Kuang *et al.* (PMID: 26854927) described a large family of European descent (TAA337) with 8 cases of acute aortic dissection and a combined LOD score of 3. Ascending aorta pathological studies from an affected individual in this family revealed loss of smooth muscle cells between elastin fibers. The disease penetrance in family TAA337 was specific to males only as female carriers, despite being in their sixth and seventh decades of life at time of report, did not show symptoms of aortopathy. Therefore, only five affected individuals were applied to the segregation score. A second family (MS300) was also reported to be affected by aortic root dilatation and had three members with the variant FOXE3*:p.Gly137Asp, however, there were not enough segregations in this family to qualify as scorable evidence as per the ClinGen Gene-Disease Validity Standard Operating Procedures (version 12). This gene-disease relationship is further supported by experimental data in the form of tissue expression, zebrafish and mouse models. While bulk tissue gene expression data from the GTEx Portal indicates *FOXE3* to be expressed in the aorta, the value of this evidence was reduced as the level of gene expression in the aorta (0.097 TPM) was not high compared to other tissue types (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Kuang *et al* knocked down Foxe3 using morpholinos in Zebrafish and showed that it disrupts aortic arch development while knockdown of p53, a key regulator of SMC apoptosis, rescued this phenotype (PMID: 26854927). Kuang *et al* also showed transverse aortic constriction (TAC) led to altered aortic remodeling and increased rupture in Foxe3 knockout mice and that inhibition of p53 rescued aortic developmental defects and aberrant aortic remodeling in the Foxe3 knockout mice that underwent TAC (PMID: 26854927). A loss of function disease mechanism for *FOXE3*-related FTAAD is uncertain as other spontaneous and targeted mouse models of homozygous Foxe3 disruption recapitulated human patient ocular features anomalies without cardiac abnormalities or aortopathy (PMIDs: 10652278, 16199865). The number of published cases of *FOXE3*-related FTAAD post 2016 is very limited. A missense variant *FOXE3*:p.R90L was mentioned in a cohort of thoracic aortic aneurysm and dissection patients (Bulat A. Ziganshin, PHD thesis 2024, https://doi.org/10.7916/7xzc-gg92), however, it was not included in the curation as it is not rare in the population (GrpMax AF >0.0001) and it was also reported in patients presenting with autosomal recessive primary aphakia and autosomal dominant Peters’ anomaly, both without FTAAD (PMID: 25504734 and AJ Churchill *et al.* Investigative Ophthalmology & Visual Science 2002). Queries to submitters of several *FOXE3* variants in ClinVar tagged with the condition “cardiac phenotype” did not result in any phenotypic association to FTAAD (Clinvar IDs: SCV006556805.1 (VCV001998828.5), SCV005025916.1 (VCV001009731.10), SCV003758557.3 (VCV000427852.14), SCV005584152.1 (VCV000861248.9), SCV005025950.1 (VCV003226204.1)). Finally, an extensive literature search did not reveal evidence of increased burden of rare variants in *FOXE3* within relevant FTAAD/aortopathy patient cohorts or biobank studies (PMIDs: 37426142, 38256594). This gene-disease pair was originally evaluated by the Heritable Thoracic Aortic Aneurysm and Dissection Gene Curation Expert Panel on June 15th, 2016. It was reevaluated on June 19th, 2026. As a result of this reevaluation, the classification was downgraded from MODERATE to LIMITED, based on limited case-level evidence as well as the lack of new genetic and experimental evidence clearly attributing *FOXE3* with FTAAD. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease Gene Curation Expert Panel on June 19th, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0011414

Submitter: Orphanet

Inheritance Pattern: SD

Disease ID:MONDO:0019503

Submitter: ClinGen

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).