FOXE1

protein-coding

forkhead box E1, the group of Forkhead boxes

Gene summary

This intronless gene encodes a protein that belongs to the forkhead family of transcription factors. Members of this family contain a conserved 100-amino acid DNA-binding 'forkhead' domain. The encoded protein functions as a thyroid transcription factor that plays a role in thyroid morphogenesis. Mutations in this gene are associated with the Bamforth-Lazarus syndrome, and with susceptibility to nonmedullary thyroid cancer-4. [provided by RefSeq, Nov 2016]

Previous symbols:

FKHL15
TITF2
FOXE2

MANE transcript

NM_004473.4

Inheritance

AR, AD

ClinVar variants

P:6U:76B:28

Top phenotype

Thyroid cancer, nonmedullary 4; Hypothyroidism, thyroidal, with spiky hair and cleft palate (Bamforth-Lazarus syndrome)

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr9:97,853,226-97,856,717

External References & Databases

Ensembl (ENSG00000178919)

Transcript & Mutation Effects

hg38 • Region Span ~3.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bamforth-Lazarus syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009437

Submitter: Orphanet

Bamforth-Lazarus syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009437

Submitter: Ambry Genetics

Bamforth-Lazarus syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009437

Submitter: PanelApp Australia

Bamforth-Lazarus syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009437

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Bamforth-Lazarus syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009437

Submitter: Labcorp Genetics (formerly Invitae)

Bamforth-Lazarus syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009437

Submitter: G2P

Bamforth-Lazarus syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009437

Submitter: ClinGen

FOXE1 was first reported in relation to AR FOXE1-related athyreosis with cleft palate in 1998 (Clifton-Bligh et al., PMID: 9697705). FOXE1-related athyreosis with cleft palate, also known as Bamforth-Lazarus syndrome, is a rare disorder characterized by congenital hypothyroidism due to thyroid agenesis or thyroid hypoplasia, cleft palate, and spiky hair. Variants in FOXE1 have been reported in individuals with the following disease entities: Bamforth-Lazarus syndrome, thyroid cancer, nonmedullary 4, and athyreosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and inheritance pattern. Therefore, the following disease entities have been split into three disease entities, Bamforth-Lazarus syndrome (MIM:241850), thyroid cancer, nonmedullary 4 (MIM:616534), and athyreosis (no MIM). The split curations for AD thyroid cancer, nonmedullary 4 and athyreosis will be curated separately by a different GCEP. Five missense and one frameshift variants that have been reported in six probands in six publications (PMIDs: 9697705, 12165566, 16882747, 20453517, 24219130, 35963604) are included in this curation. The mechanism of pathogenicity is unknown at this time. This gene-disease relationship is also supported by functional alteration of patient cells, animal models, and expression data (PMIDs: 9697705, 9697704, 15494458, 21177256). In summary, there is definitive evidence to support the relationship between FOXE1 and Bamforth-Lazarus syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date May 16th, 2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Thyroid cancer, nonmedullary 4; Hypothyroidism, thyroidal, with spiky hair and cleft palate (Bamforth-Lazarus syndrome)AD/AR

Manifestation: Craniofacial; Dermatologic; Endocrine; Musculoskeletal; Oncologic

Intervention: Endocrine; Oncologic

Rationale: For Thyroid cancer, nonmedullary 4, individuals have been described as being susceptible to nonmedullary thyroid cancer, and awareness may allow early surveillance, diagnosis, and management; For Hypothyroidism, thyroidal, with spiky hair and cleft palate (Bamforth-Lazarus syndrome), the condition may be clinically recognizable, but recognition and prompt treatment of hypothyroidism can be beneficial

Refs: 2918525; 8320710; 9697705; 12165566; 16882747; 17717707; 17318017; 19779022; 20484477; 20453517; 20094846; 21981779; 21311165; 25381600

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXE1 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 56

not specifiedTotal: 26

not providedTotal: 24

Bamforth-Lazarus syndromeTotal: 16

FOXE1-related disorderTotal: 14

Thyroid cancer, nonmedullary, 4Total: 5

congenital hypothyreodismTotal: 1

Congenital hypothyroidismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004473.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				21 clinvar	3 clinvar	24
missense	3 clinvar	2 clinvar	74 clinvar	2 clinvar	2 clinvar	83
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	4	2	76	23	5	110

Highest pathogenic variant AF is 0.000006582065

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004473.4	RefSeq	NP_004464.2	1	MANE Select
ENST00000375123.5	Ensembl	ENSP00000364265.3	1	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxe1	Danio rerio	Structure: ceratobranchial cartilage Quality: deformed abnormal

Gene / Model

Organism

Observed Phenotype

foxe1

Danio rerio

Structure: ceratobranchial cartilage

Quality: deformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription by RNA polymerase II
thyroid hormone generation
anatomical structure morphogenesis
cell migration

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375123
Coding exons: 1
Length: 3451
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.315	149	160	0.930	0.00000739	2256
Missense (PolyPhen)		55	63.26	0.86943		738
Synonymous	0.328	70	73.6	0.951	0.00000363	840
Loss of Function	2.11	0	5.20	0.00	2.21e-7	84

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription. Involved in proper palate formation, most probably through the expression of MSX1 and TGFB3 genes which are direct targets of this transcription factor. Also implicated in thyroid gland morphogenesis. May indirectly play a role in cell growth and migration through the regulation of WNT5A expression. {ECO:0000269|PubMed:12165566, ECO:0000269|PubMed:16882747, ECO:0000269|PubMed:20094846, ECO:0000269|PubMed:20484477, ECO:0000269|PubMed:21177256, ECO:0000269|PubMed:24219130, ECO:0000269|PubMed:25381600, ECO:0000269|PubMed:9697705}.;
Disease: DISEASE: Bamforth-Lazarus syndrome (BLS) [MIM:241850]: A disease characterized by thyroid agenesis, cleft palate and choanal atresia. {ECO:0000269|PubMed:12165566, ECO:0000269|PubMed:21177256, ECO:0000269|PubMed:24219130, ECO:0000269|PubMed:9697705}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thyroid cancer, non-medullary, 4 (NMTC4) [MIM:616534]: A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. {ECO:0000269|PubMed:25381600}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.325

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium