FOXE3

Summary

FOXE3 (forkhead box E3, HGNC:3808) is a protein-coding gene on chromosome 1p33, encoding Forkhead box protein E3 (Q13461). Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle.

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.

Source: NCBI Gene 2301 — RefSeq curated summary.

At a glance

• Gene–disease (curated): anterior segment dysgenesis (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 396 total — 8 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 80
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_012186

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3808
Approved symbol	FOXE3
Name	forkhead box E3
Location	1p33
Locus type	gene with protein product
Status	Approved
Aliases	FREAC8
Ensembl gene	ENSG00000186790
Ensembl biotype	protein_coding
OMIM	601094
Entrez	2301

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000335071

RefSeq mRNA: 1 — MANE Select: NM_012186 NM_012186

CCDS: CCDS550

Canonical transcript exons

ENST00000335071 — 1 exons

Exon	Start	End
ENSE00001338032	47416285	47418052

Expression profiles

Bgee: expression breadth broad, 36 present calls, max score 86.26.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1019 / max 26.2137, expressed in 52 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2780	0.1019	52

Top tissues by expression

215 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.44	gold quality
mucosa of transverse colon	UBERON:0004991	56.82	gold quality
cranial nerve II	UBERON:0000941	50.98	silver quality
trabecular bone tissue	UBERON:0002483	50.37	gold quality
tibial nerve	UBERON:0001323	49.36	gold quality
putamen	UBERON:0001874	49.31	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
metanephric glomerulus	UBERON:0004736	47.76	gold quality
renal glomerulus	UBERON:0000074	47.57	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
tendon of biceps brachii	UBERON:0008188	46.99	gold quality
nephron tubule	UBERON:0001231	46.71	gold quality
colonic epithelium	UBERON:0000397	45.88	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
saphenous vein	UBERON:0007318	45.23	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality
nasal cavity epithelium	UBERON:0005384	44.87	gold quality
bone marrow cell	CL:0002092	44.17	gold quality
cerebellar cortex	UBERON:0002129	43.52	gold quality
cerebellar hemisphere	UBERON:0002245	43.46	gold quality
cerebellum	UBERON:0002037	43.42	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
metanephros	UBERON:0000081	42.68	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
middle temporal gyrus	UBERON:0002771	42.38	gold quality
medulla oblongata	UBERON:0001896	41.74	gold quality
granulocyte	CL:0000094	41.68	silver quality
cartilage tissue	UBERON:0002418	41.64	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.33

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX6, SMAD9, ZEB2

miRNA regulators (miRDB)

28 targeting FOXE3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-5585-5P	97.95	68.80	1024
HSA-MIR-4433A-3P	97.75	62.82	1435
HSA-MIR-450B-3P	97.56	66.12	512
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-769-3P	97.06	64.83	464
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-4750-3P	96.65	64.38	512
HSA-MIR-7847-3P	96.63	64.58	952
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-4769-5P	95.37	66.09	570
HSA-MIR-6784-5P	84.56	60.91	126

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• FOXE3 is essential for closure of the lens vesicle during eye development and for lens epithelial survival and proliferation. (PMID:10652278)
• Role very early in the lens developmental program, perhaps earlier than any role recognized elsewhere for this gene. (PMID:16826526)
• findings suggest that mutations in FOXE3 can give rise to a broad spectrum of eye anomalies, largely, but not exclusively related to lens development, and that both dominant and recessive inheritance patterns can be represented (PMID:19708017)
• Recessive mutations in FOXE3 were found in four of 26 probands affected with bilateral microphthalmia (15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype). (PMID:20140963)
• FOXE3 is responsible for the early developmental arrest of the lens placode, and the complete loss of a functional FOXE3 protein results in primary aphakia. (PMID:20361012)
• Using autoantibodies from systemic sclerosis (SSc) patients, two anti-CENP-A-specific motifs were defined in its immunodominant epitope Ap17-30. One of these motifs matched residues 53-62 of FOXE3, a protein not previously implicated in SSc. (PMID:20630806)
• This is the fourth report detailing homozygous FOXE3 mutations causing anterior segment abnormalities in human patients. (PMID:20664696)
• Mutations in several transcription factors associated with aniridia and congenital cataract, FOXE3, (PAX6), PITX2, and PITX3 genes, were examined. (PMID:20806047)
• Autosomal-dominant mutations within FOXE3 cause anterior segment dysgenesis and has important clinical utility, especially for the diagnosis of mildly affected patients. (PMID:21150893)
• The FOXE3 mutation detected in c.601 G > A, predicting p.Val201Met which were not yet been included in public databases, but has previously been reported in both A/M patients. (PMID:22204637)
• shRNA-mediated gene silencing of FOXE3 could significantly inhibit cell growth and induce the G1-phase arrest in human lens epithelial cell line-3 cells. (PMID:22527307)
• This study demonstrates that a cluster of patients with sclerocornea, aphakia, and microphthalmia in a small Mexican village is due to a FOXE3 p.Y98H founder mutation. (PMID:24019743)
• Our results indicate that the FOXE3 p.Val201Met allele is associated with eye defects (OR = 3.5), suggesting its involvement as an ocular malformation risk factor. (PMID:24689660)
• This is the first functional evidence demonstrating that FOXE3 mutations identified in patients impair protein function with differential effects. (PMID:25504734)
• FOXE3 mutations lead to a reduced number of aortic smooth muscle cells (SMCs) during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces. (PMID:26854927)
• Data show that DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) is a transcriptional target of forkhead box protein E3 (FOXE3) in a pathway that is crucial for the development of the anterior segment of the eye. (PMID:27218149)
• Only one novel missense mutation in exon 1 of FOXE3 (Chr1:47,882,459, c.472G>C, p.Gly158Arg) was identified being homozygous in the three affected and heterozygous in the two unaffected, which was confirmed by Sanger sequencing. (PMID:27669367)
• Although congenital aphakia is known to be caused by mutations in the FOXE3 gene, the results of lack of coding mutation in this patient suggests a possible genetic heterogeneity of the disease. (PMID:28805541)
• To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. (PMID:29136273)
• Comparative analysis of this RNA-seq data with iSyTE data identified several lens-enriched genes to be down-regulated in foxe3 indel mutants. We also noted upregulation of lgsn and crygmxl2 and downregulation of fmodb and cx43.4, genes that are expressed in the zebrafish lens, but that are not yet associated with an eye phenotype in humans. (PMID:29713869)
• The sclerocornea-microphthalmia-aphakia complex is a severe malformative ocular phenotype resulting from mutations in the FOXE3 transcription factor. To date, patients from at least 14 families with this uncommon ocular disorder have been described. The identification of 2 novel pathogenic variants in our patients expands the mutational spectrum in FOXE3-related congenital eye disorders. (PMID:29878917)
• Identification of FOXE3 transcription factor as a potent oncogenic factor in triple-negative breast cancer. (PMID:31831170)
• Pathogenic variants of AIPL1, MERTK, GUCY2D, and FOXE3 in Pakistani families with clinically heterogeneous eye diseases. (PMID:32976546)
• Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders. (PMID:34046667)
• FOXO1-regulated lncRNA CYP1B1-AS1 suppresses breast cancer cell proliferation by inhibiting neddylation. (PMID:37640964)
• Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia. (PMID:37758467)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Foxe3	ENSMUSG00000044518
rattus_norvegicus	Foxe3	ENSRNOG00000007770

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein E3 — Q13461 (reviewed: Q13461)

Alternative names: Forkhead-related protein FKHL12, Forkhead-related transcription factor 8

All UniProt accessions (2): Q13461, A0A0A1EII5

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle. During lens development, controls the ratio of the lens fiber cells to the cells of the anterior lens epithelium by regulating the rate of proliferation and differentiation. Controls lens vesicle closure and subsequent separation of the lens vesicle from ectoderm. Controls the expression of DNAJB1 in a pathway that is crucial for the development of the anterior segment of the eye.

Subcellular location. Nucleus.

Disease relevance. Anterior segment dysgenesis 2 (ASGD2) [MIM:610256] A form of anterior segment dysgenesis, a group of defects affecting anterior structures of the eye including cornea, iris, lens, trabecular meshwork, and Schlemm canal. Anterior segment dysgeneses result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to components of the anterior chamber during eye development. Different anterior segment anomalies may exist alone or in combination, including iris hypoplasia, enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Clinical conditions falling within the phenotypic spectrum of anterior segment dysgeneses include aniridia, Axenfeld anomaly, Reiger anomaly/syndrome, Peters anomaly, and iridogoniodysgenesis. Some ASGD2 patients show congenital primary aphakia, a defect caused by eye development arrest around the 4th-5th week of gestation. This prevents the formation of any lens structure and leads to severe secondary ocular anomalies, including a complete aplasia of the anterior segment of the eye. In contrast, in secondary aphakic eyes, lens induction has occurred, and the lens vesicle has developed to some degree but finally has progressively resorbed perinatally, leading, therefore, to less severe ocular defects. ASGD2 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Cataract 34, multiple types (CTRCT34) [MIM:612968] An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. The disease is caused by variants affecting the gene represented in this entry. Aortic aneurysm, familial thoracic 11 (AAT11) [MIM:617349] A form of thoracic aortic aneurysm, a disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as ‘medial necrosis’ or ‘Erdheim cystic medial necrosis’ in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. Disease susceptibility is associated with variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_036318* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR018122	TF_fork_head_CS_1	Conserved_site
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050211	FOX_domain-containing	Family

Pfam: PF00250

UniProt features (15 total): sequence variant 10, chain 1, DNA-binding region 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13461-F1	66.68	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 223 (showing top): GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, SRF_Q5_01, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, SRF_C, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MRNA_TRANSCRIPTION, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_SENSORY_ORGAN_MORPHOGENESIS, GOBP_EPITHELIAL_CELL_PROLIFERATION

GO Biological Process (22): eye development (GO:0001654), lens development in camera-type eye (GO:0002088), trabecular meshwork development (GO:0002930), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), anatomical structure morphogenesis (GO:0009653), cell differentiation (GO:0030154), mRNA transcription by RNA polymerase II (GO:0042789), negative regulation of apoptotic process (GO:0043066), cell development (GO:0048468), epithelial cell proliferation (GO:0050673), regulation of cell cycle (GO:0051726), iris morphogenesis (GO:0061072), ciliary body morphogenesis (GO:0061073), cornea development in camera-type eye (GO:0061303), negative regulation of lens fiber cell differentiation (GO:1902747), positive regulation of lens epithelial cell proliferation (GO:2001111), regulation of DNA-templated transcription (GO:0006355), camera-type eye development (GO:0043010), animal organ development (GO:0048513), system development (GO:0048731), positive regulation of epithelial cell proliferation (GO:0050679)

GO Molecular Function (5): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	5
camera-type eye development	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
cellular developmental process	2
anatomical structure morphogenesis	2
camera-type eye morphogenesis	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
sensory organ development	1
visual system development	1
tissue development	1
developmental process	1
mRNA transcription	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell differentiation	1
cell population proliferation	1
cell cycle	1
regulation of cellular process	1
negative regulation of epithelial cell differentiation	1
negative regulation of multicellular organismal process	1
lens fiber cell differentiation	1
regulation of lens fiber cell differentiation	1
positive regulation of epithelial cell proliferation	1
lens epithelial cell proliferation	1
regulation of lens epithelial cell proliferation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
eye development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
DNA binding	1
chromosome	1

Protein interactions and networks

STRING

994 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXE3	GPR161	Q8N6U8	957
FOXE3	PITX3	O75364	934
FOXE3	PAX6	P26367	721
FOXE3	CRYGS	P22914	642
FOXE3	GJA8	P48165	618
FOXE3	B3GLCT	Q6Y288	617
FOXE3	CRYAA	P02489	611
FOXE3	GJA3	Q9Y6H8	603
FOXE3	PITX2	Q99697	601
FOXE3	CRYBB2	P43320	597
FOXE3	CRYBA4	P53673	593
FOXE3	BFSP2	Q13515	583
FOXE3	MAF	O75444	580
FOXE3	CRYBB3	P26998	575
FOXE3	BFSP1	Q12934	571

IntAct

2 interactions, top by confidence:

A	B	Type	Score
FOXE3	C1QBP	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): C1QBP (Affinity Capture-MS), C5orf22 (Affinity Capture-MS), TNPO1 (Affinity Capture-MS), HIST2H3PS2 (Affinity Capture-MS), PHF10 (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), BAG1 (Affinity Capture-MS)

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A6NIN4, D3YXK1, G3UXB3, O15370, O15522, O35392, O70218, O70220, O89113, P0DPE3, P12980, P17542, P22091, P28283, P82976, Q04890, Q05916, Q05917, Q13461, Q14V87, Q15270, Q19A40, Q5T230, Q5VY09, Q63244, Q6F5E0, Q6SPE9, Q6SPF0, Q7RTU7, Q80WY3, Q8TD94, Q8WY41, Q8WZ71, Q91XV7, Q96Q04

Diamond homologs: A0A078BQN7, A0A1W2PRP0, A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, F1R8Z9, O00358, O17617, O43638, O54743, O60129, O88470, P32027, P32028, P32030, P32315, P42128, P55316, P56260, P58012, P79772, P85037, P91278, Q00939, Q01167, Q02360, Q12946, Q12947, Q12948, Q12950, Q12951, Q12952, Q13461, Q19802, Q1A1A1, Q1A1A2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

396 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	7
Uncertain significance	251
Likely benign	100
Benign	7

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1077103	NM_012186.3(FOXE3):c.21_24del (p.Met7fs)	Pathogenic
1077109	NM_012186.3(FOXE3):c.959G>C (p.Ter320Ser)	Pathogenic
1077110	NM_012186.3(FOXE3):c.958T>C (p.Ter320Arg)	Pathogenic
1428067	NM_012186.3(FOXE3):c.555dup (p.Phe186fs)	Pathogenic
2947078	NM_012186.3(FOXE3):c.706G>T (p.Glu236Ter)	Pathogenic
372170	NM_012186.3(FOXE3):c.307G>A (p.Glu103Lys)	Pathogenic
4783515	NM_012186.3(FOXE3):c.472G>C (p.Gly158Arg)	Pathogenic
8448	NM_012186.3(FOXE3):c.720C>A (p.Cys240Ter)	Pathogenic
1077105	NM_012186.3(FOXE3):c.286G>A (p.Ala96Thr)	Likely pathogenic
1305850	NM_012186.3(FOXE3):c.473G>A (p.Gly158Asp)	Likely pathogenic
1424381	NM_012186.3(FOXE3):c.387C>G (p.Phe129Leu)	Likely pathogenic
2440302	NM_012186.3(FOXE3):c.724del (p.Ala242fs)	Likely pathogenic
2632844	NM_012186.3(FOXE3):c.456dup (p.Asp153fs)	Likely pathogenic
383925	NM_012186.3(FOXE3):c.224C>T (p.Ser75Leu)	Likely pathogenic
983475	NM_012186.3(FOXE3):c.289A>G (p.Ile97Val)	Likely pathogenic

SpliceAI

103 predictions. Top by Δscore:

Variant	Effect	Δscore
1:47416646:A:AG	acceptor_gain	0.7200
1:47416647:G:GG	acceptor_gain	0.7200
1:47416639:C:G	acceptor_gain	0.6900
1:47416640:C:A	acceptor_gain	0.6600
1:47416647:GCCC:G	acceptor_gain	0.6600
1:47416642:C:CA	acceptor_gain	0.6400
1:47416638:A:AG	acceptor_gain	0.6200
1:47416638:ACC:A	acceptor_gain	0.6000
1:47416638:ACCGC:A	acceptor_gain	0.6000
1:47416647:GCC:G	acceptor_gain	0.5700
1:47416706:A:AC	acceptor_gain	0.5600
1:47416646:AGCCC:A	acceptor_gain	0.5000
1:47416647:GCCCG:G	acceptor_gain	0.5000
1:47416647:GC:G	acceptor_gain	0.4900
1:47416642:CGACA:C	acceptor_loss	0.4700
1:47416643:GACA:G	acceptor_loss	0.4700
1:47416644:ACAG:A	acceptor_loss	0.4700
1:47416645:CAG:C	acceptor_loss	0.4700
1:47416646:AGCC:A	acceptor_loss	0.4700
1:47416704:TCA:T	acceptor_gain	0.4000
1:47417363:T:TA	acceptor_gain	0.4000
1:47417521:ACTT:A	acceptor_gain	0.4000
1:47417528:AGCGC:A	acceptor_gain	0.4000
1:47416641:GCGAC:G	acceptor_loss	0.3900
1:47416630:T:TA	acceptor_loss	0.3800
1:47416560:T:TA	acceptor_gain	0.3700
1:47417078:G:GA	acceptor_gain	0.3600
1:47416610:C:A	acceptor_gain	0.3500
1:47417531:GCCCC:G	acceptor_gain	0.3500
1:47417532:CCCCC:C	acceptor_gain	0.3500

AlphaMissense

1996 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:47416539:C:T	S75L	1.000
1:47416541:T:C	Y76H	1.000
1:47416545:T:A	I77N	1.000
1:47416551:T:A	L79H	1.000
1:47416551:T:C	L79P	1.000
1:47416554:T:A	I80N	1.000
1:47416596:T:A	L94Q	1.000
1:47416605:T:A	I97N	1.000
1:47416613:T:C	F100L	1.000
1:47416614:T:C	F100S	1.000
1:47416615:C:A	F100L	1.000
1:47416615:C:G	F100L	1.000
1:47416617:T:A	I101N	1.000
1:47416617:T:G	I101S	1.000
1:47416628:T:A	F105I	1.000
1:47416628:T:C	F105L	1.000
1:47416629:T:C	F105S	1.000
1:47416630:T:A	F105L	1.000
1:47416630:T:G	F105L	1.000
1:47416634:T:C	F107L	1.000
1:47416636:C:A	F107L	1.000
1:47416636:C:G	F107L	1.000
1:47416658:T:A	W115R	1.000
1:47416658:T:C	W115R	1.000
1:47416660:G:C	W115C	1.000
1:47416660:G:T	W115C	1.000
1:47416664:A:G	N117D	1.000
1:47416665:A:T	N117I	1.000
1:47416666:C:A	N117K	1.000
1:47416666:C:G	N117K	1.000

dbSNP variants (sampled 300 via entrez): RS1000137599 (1:47414415 G>C), RS1001124481 (1:47415105 C>A,T), RS1001281370 (1:47414723 A>C,T), RS1002420215 (1:47418264 G>T), RS1003465420 (1:47417522 C>G), RS1003622922 (1:47416243 G>A,C,T), RS1003686562 (1:47416942 C>A,T), RS1003802007 (1:47417128 G>A,C,T), RS1005614509 (1:47417544 C>T), RS1006003867 (1:47415416 A>C,G), RS1006047408 (1:47416386 C>T), RS1006082706 (1:47417839 C>T), RS1006096740 (1:47416244 GC>G,GCC), RS1006365722 (1:47415120 T>C), RS1007713128 (1:47415419 C>G,T)

Disease associations

OMIM: gene MIM:601094 | disease phenotypes: MIM:610256, MIM:107250, MIM:612968, MIM:607086, MIM:617349, MIM:604229

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital primary aphakia	Definitive	Autosomal dominant
cataract	Definitive	Autosomal dominant
anterior segment dysgenesis 1	Strong	Autosomal dominant
aortic aneurysm, familial thoracic 11, susceptibility to	Strong	Autosomal dominant
familial thoracic aortic aneurysm and aortic dissection	Moderate	Unknown
Peters anomaly	Supportive	Autosomal dominant
anterior segment dysgenesis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
anterior segment dysgenesis	Definitive	SD
familial thoracic aortic aneurysm and aortic dissection	Moderate	AD

Mondo (9): congenital primary aphakia (MONDO:0012456), anterior segment dysgenesis (MONDO:0019503), cataract 34 multiple types (MONDO:0013067), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), aortic aneurysm, familial thoracic 11, susceptibility to (MONDO:0044301), anterior segment dysgenesis 1 (MONDO:0007138), aortic aneurysm, familial thoracic 1 (MONDO:0024559), Peters anomaly (MONDO:0011414), cataract (MONDO:0005129)

Orphanet (6): Congenital primary aphakia (Orphanet:83461), Anterior segment developmental anomaly (Orphanet:88632), Early onset non-syndromic cataract (Orphanet:91492), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Familial aortic dissection (Orphanet:229), Peters anomaly (Orphanet:708)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000518	Cataract
HP:0000523	Subcapsular cataract
HP:0000525	Abnormality iris morphology
HP:0000526	Aniridia
HP:0000541	Retinal detachment
HP:0000568	Microphthalmia
HP:0000588	Optic disc coloboma
HP:0000589	Coloboma
HP:0000639	Nystagmus
HP:0000647	Sclerocornea
HP:0000659	Peters anomaly
HP:0000667	Phthisis bulbi
HP:0000766	Abnormal sternum morphology
HP:0000822	Hypertension
HP:0000965	Cutis marmorata
HP:0000978	Bruising susceptibility
HP:0001087	Developmental glaucoma
HP:0001166	Arachnodactyly
HP:0001297	Stroke
HP:0001640	Cardiomegaly
HP:0001643	Patent ductus arteriosus

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST010696_1	Cortical thickness (min-P)	7.000000e-09
GCST010697_11	Cortical surface area (min-P)	3.000000e-10
GCST010698_70	Subcortical volume (min-P)	1.000000e-14
GCST010699_77	Brain morphology (min-P)	4.000000e-17
GCST010700_17	Cortical thickness (MOSTest)	4.000000e-12
GCST010701_126	Cortical surface area (MOSTest)	1.000000e-10
GCST010702_41	Subcortical volume (MOSTest)	2.000000e-10
GCST010703_86	Brain morphology (MOSTest)	2.000000e-103

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002386	Cataract	C11.510.245
C562834	Aortic Aneurysm, Familial Thoracic 1 (supp.)
C537786	Aphakia, congenital primary (supp.)
C567835	Cataract, Autosomal Recessive Congenital 3 (supp.)
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
bisphenol F	affects cotreatment, increases methylation	1
licochalcone B	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1Z4	SEES3-1V human FOXE3, clone1	Embryonic stem cell	Male
CVCL_A1Z5	SEES3-1V human FOXE3, clone2	Embryonic stem cell	Male
CVCL_A1Z6	SEES3-1V human FOXE3, clone3	Embryonic stem cell	Male
CVCL_F0SZ	IOCVi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00273221	PHASE4	UNKNOWN	Combined Phacotube vs Phacotrabeculectomy:A Randomized Controlled Trial
NCT00312299	PHASE4	COMPLETED	Posterior Capsule Opacification Study
NCT00345046	PHASE4	COMPLETED	A Comparison of Three Different Formulations of Prednisolone Acetate 1%
NCT00347243	PHASE4	COMPLETED	Wavefront Analisys and Contrast Sensitivity of Spherical and Aspherical Intraocular Lenses
NCT00347503	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients
NCT00348244	PHASE4	COMPLETED	Ketorolac vs. Steroid in the Prevention of CME
NCT00348270	PHASE4	COMPLETED	Comparison of the Quality of Vision Provided by AMO Tecnis Z9000 and Alcon Laboratories MA60 Acrysof Posterior Chamber Intraocular Lenses
NCT00348582	PHASE4	COMPLETED	Acular LS vs. Nevanac in Post op Inflammation Following Cataract Surgery
NCT00348621	PHASE4	COMPLETED	A Study of Interventions to Reduce Disability From Visual Loss in Nursing Home Residents
NCT00349583	PHASE4	COMPLETED	Efficacy of Topical Cyclosporine Versus Tears for Improving Visual Outcomes Following Multifocal IOL Implantation
NCT00355446	PHASE4	COMPLETED	Bioavailability of Bimatoprost Ophthalmic Solution in Human Aqueous.
NCT00386438	PHASE4	COMPLETED	Efficacy of Honan Balloon in Intraocular Pressure Reduction Before Phacoemulsification
NCT00392275	PHASE4	COMPLETED	Penetrance of Third Generation Fluoroquinolones in Eyes With Functioning Filtering Blebs
NCT00428363	PHASE4	COMPLETED	Effect of Optic Edge Design in a Silicone Intraocular Lens on Posterior Capsule Opacification
NCT00449267	PHASE4	COMPLETED	Aurolab Hydrophobic Foldable Intraocular Lens Study
NCT00459303	PHASE4	COMPLETED	Comparison of Functional Vision Provided by AMO Tecnis Z9000 and Alcon SA60AT Acrysof
NCT00469690	PHASE4	COMPLETED	Aqueous Concentrations and PGE2 Inhibition of Ketorolac 0.4% vs. Bromfenac 0.09% in Cataract Patients: Trough Drug Effects
NCT00576485	PHASE4	COMPLETED	Spherical Aberration and Contrast Sensitivity in IOLs
NCT00612729	PHASE4	COMPLETED	Light Filters in Intraocular Lenses (IOLs) and Its Influence on Colour and Contrast Vision.
NCT00612781	PHASE4	COMPLETED	Yellow Versus White Study
NCT00630019	PHASE4	COMPLETED	Ocular Tissue Levels of 1.5% Levofloxacin Ophthalmic Solution Compared to an Active Comparator
NCT00673803	PHASE4	COMPLETED	Influence of Two Different Preloaded Intraocular Lens (IOLs) on Posterior Capsule Opacification
NCT00684138	PHASE4	COMPLETED	ACRYSOF® ReSTOR® Aspheric +3.0 D Add Power Intraocular Lens (IOL)
NCT00698724	PHASE4	COMPLETED	Comparing Optical Coherence Tomography (OCT) and Visual Acuity Outcomes in Subjects Undergoing Cataract Surgery, Who Receive Xibrom Ophthalmic Solution and Standard Presurgical Care vs. Xibrom Ophthalmic Solution Plus Prednisolone Acetate 1% and Standard Presurgical Care
NCT00710905	PHASE4	TERMINATED	Visual Function With Contralateral AcrySof® ReSTOR® Aspheric SN6AD1 and SN6AD3
NCT00710931	PHASE4	COMPLETED	Visual Function With Bilateral AcrySof® ReSTOR® Aspheric SN6AD1
NCT00711347	PHASE4	COMPLETED	Intraoperative Floppy Iris Syndrome
NCT00712244	PHASE4	COMPLETED	DisCoVisc Versus DuoVisc, Healon5 and AmVisc Plus
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00719732	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof ReSTOR Aspheric +3
NCT00721253	PHASE4	COMPLETED	Visual Outcomes of Subjects Bilaterally Implanted With ReSTOR Aspheric +4 vs. Tecnis or Acri.LISA
NCT00731640	PHASE4	COMPLETED	Contralateral ReSTOR / Monofocal or Phakic Eye
NCT00732030	PHASE4	COMPLETED	Low Cylinder Toric
NCT00758199	PHASE4	COMPLETED	Determination of Optimum Duration of Treatment With Bromfenac (Xibrom) Eyedrops Following Cataract Surgery
NCT00760058	PHASE4	WITHDRAWN	Visual Outcome and Visual Quality After Bilateral Implantation of the AcrySof® IQ IOL Compared to MI60® and Tecnis® IOL
NCT00760487	PHASE4	COMPLETED	Visual Function After Implantation of Bilateral AcrySof® Toric Natural Intraocular Lens
NCT00761488	PHASE4	WITHDRAWN	Recommendations for Monitoring Clinical Experience Following Implantation of the AcrySof® Toric
NCT00763360	PHASE4	COMPLETED	To Compare the Ability of DiscoVisc® OVD to Protect the Corneal Endothelium and Maintain Anterior Chamber Space With Healon® and Amvisc® PLUS During Cataract Surgery.
NCT00786370	PHASE4	COMPLETED	Dexmedetomidine vs. Propofol for Cataract Surgery
NCT00786565	PHASE4	COMPLETED	Clinical Evaluation of a New Aspheric Intraocular Lens.