Mendeliome
Gene: FOXE3 Green List (high evidence)Green List (high evidence)
Associated with {Aortic aneurysm, familial thoracic 11, susceptibility to} MIM#617349 in OMIM. All reported cases come from All cases reported in PMID: 26854927 (Kuang et al 2016) are heterozygous so the MONOALLELIC mode of inheritance is appropriate for the Thoracic aortic aneurysms and acute aortic dissection phenotype.
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:
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).
For cataracts especially a mode of inheritance of Both mono and biallelic is appropriate.Created: 9 Sep 2021, 9:35 a.m. | Last Modified: 9 Sep 2021, 9:35 a.m.
Panel Version: 0.9125
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
Anterior segment dysgenesis 2, multiple subtypes, MIM#610256; Cataract 34, multiple types, MIM#612968; Aortic aneurysm, familial thoracic 11, susceptibility to}, MIM#617349
Publications
Gene: foxe3 has been classified as Green List (High Evidence).
Phenotypes for gene: FOXE3 were changed from to Anterior segment dysgenesis 2, multiple subtypes, MIM#610256; Cataract 34, multiple types, MIM#612968; Aortic aneurysm, familial thoracic 11, susceptibility to}, MIM#617349
Publications for gene: FOXE3 were set to
Mode of inheritance for gene: FOXE3 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
gene: FOXE3 was added gene: FOXE3 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: FOXE3 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.