FOXE3

Chr 1ADAR

forkhead box E3

Also known as: AAT11, ASGD2, CATC3, CTRCT34, FKHL12, FREAC8

NCBI Gene: 2301 ENSG00000186790 UniProt: Q13461 OMIM: 601094

FOXE3 encodes a lens-specific transcription factor that controls lens epithelial cell growth, proliferation, and differentiation during eye development. Mutations cause anterior segment dysgenesis, congenital cataracts, and congenital primary aphakia, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene primarily affects ocular development, though some mutations are also associated with familial thoracic aortic aneurysm susceptibility.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This intronless gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. The protein encoded functions as a lens-specific transcription factor and plays an important role in vertebrate lens formation. Mutations in this gene are associated with anterior segment mesenchymal dysgenesis and congenital primary aphakia. [provided by RefSeq, Dec 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 1.613 OMIM phenotypes

Clinical Summary— FOXE3

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Gene-Disease Validity (ClinGen)

familial thoracic aortic aneurysm and aortic dissection · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.18) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 388 VUS of 608 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FOXE3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.61LOEUF

pLI 0.181

Z-score 0.89

OE 0.40 (0.14–1.61)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.57Z-score

OE missense 0.83 (0.69–1.01)

76 obs / 91.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.14–1.61)

0≤0.351.4

Missense OE?0.83 (0.69–1.01)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 1 / 2.5Missense obs/exp: 76 / 91.3Syn Z: -0.95

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFOXE3-related congenital cataractOTHERAD

definitiveFOXE3-related congenital cataractOTHERAR

definitiveFOXE3-related anterior segment mesenchymal dysgenesisLOFAD

definitiveFOXE3-related congenital primary aphakiaLOFAR

This gene — mechanism propensity

0.6065th %ile

GOF

0.6540th %ile

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

LOF67% of P/LP variants are LoF

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFunctional studies identified variable effects on the protein stability, DNA binding, nuclear localization and transcriptional activity for recessive FOXE3 variants, whereas dominant alleles showed severe impairment in all areas and dominant-negative characteristics.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 34046667 ↗

ClinVar Variant Classifications

608 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic13

VUS388

Likely Benign152

Benign9

Conflicting26

Pathogenic

Likely Pathogenic

388

VUS

152

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	3	0	0	20
Likely Pathogenic	5	8	0	0	13
VUS	8	341	8	31	388
Likely Benign	0	11	3	138	152
Benign	0	1	5	3	9
Conflicting	—				26
Total	30	364	16	172	608

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap FOXE3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →