FOXC2

protein-coding

forkhead box C2, the group of Forkhead boxes

Gene summary

This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the development of mesenchymal tissues. [provided by RefSeq, Jul 2008]

Previous symbols:

FKHL14

MANE transcript

NM_005251.3

Inheritance

ClinVar variants

P:72U:203B:65

Top phenotype

Lymphedema-distichiasis syndrome

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr16:86,566,829-86,569,728

External References & Databases

Ensembl (ENSG00000176692)

Transcript & Mutation Effects

hg38 • Region Span ~2.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lymphedema-distichiasis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007922

Submitter: Genomics England PanelApp

lymphedema-distichiasis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007922

Submitter: Labcorp Genetics (formerly Invitae)

lymphedema-distichiasis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007922

Submitter: PanelApp Australia

lymphedema-distichiasis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007922

Submitter: Orphanet

lymphedema-distichiasis syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007922

Submitter: Ambry Genetics

lymphedema-distichiasis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007922

Submitter: ClinGen

*FOXC2* was first reported in relation to autosomal dominant lymphedema-distichiasis syndrome in 2000 (Fang et al., PMID: 11078474). This condition involves primary lymphedema of the lower extremities and distichiasis to various degrees. Prenatal features may include congenital heart disease, cleft palate, cystic hygroma, and nonimmune fetal hydrops. Twenty-one variants (nonsense, frameshift, and missense) that have been reported in at least 21 probands in nine publications (PMIDs: 11078474, 19394045, 21918810, 25252123, 29906362, 31974414, 20450314, 22349027, 11371511) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and *in vitro* functional assays (PMIDs: 12719382, 15322537, 27214551, 26389677, 15465483, 19398761). Foxc2 heterozygous knockout mouse models demonstrate a postnatal lymphatic and eyelash phenotype as well as dermal lymphatic hyperplasia, and a conditional Foxc2 knockout mouse model was shown to recapitulate the human lymphatic phenotype. In summary, there is definitive evidence supporting the relationship between *FOXC2* and autosomal dominant lymphedema-distichiasis 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 Prenatal GCEP on the meeting date September 26, 2023 (SOP Version 9).

lymphedema-distichiasis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007922

Submitter: G2P

Clinical Genomic Database (CGD)

Lymphedema-distichiasis syndromeAD

Manifestation: Cardiovascular; Dermatologic; Musculoskeletal; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 14269895; 3573000; 10086462; 11078474; 11499682; 11694548; 12485195; 12114478; 15523639; 17372167; 19760751; 20186799; 20301630; 20450314; 20552815; 21918810; 22349027; 22768468

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXC2 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 176

Inborn genetic diseasesTotal: 120

Distichiasis-lymphedema syndromeTotal: 54

FOXC2-related disorderTotal: 30

not specifiedTotal: 22

FOXC2-related disordersTotal: 8

Non-immune hydrops fetalisTotal: 2

Congenital ptosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005251.3. 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			14 clinvar	43 clinvar	6 clinvar	63
missense	3 clinvar	4 clinvar	186 clinvar	16 clinvar		209
nonsense	9 clinvar	10 clinvar	2 clinvar			21
start loss						0
frameshift	26 clinvar	20 clinvar	1 clinvar			47
splice donor/acceptor (+/-2bp)						0
Total	38	34	203	59	6	340

Highest pathogenic variant AF is 0.000004827412

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_005251.3	RefSeq	NP_005242.1	1	MANE Select
ENST00000649859.1	Ensembl	ENSP00000497759.1	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Heart Development
Adipogenesis
Mesodermal Commitment Pathway
BMP Signaling Pathway in Eyelid Development
EMT transition in Colorectal Cancer

Biological Process

negative regulation of transcription by RNA polymerase II
lymphangiogenesis
regulation of transcription by RNA polymerase II
mesoderm development
heart development

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320354
Coding exons: 1
Length: 1683
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	-0.251	236	225	1.05	0.0000107	3174
Missense (PolyPhen)		93	105.96	0.87769		1336
Synonymous	-4.25	159	104	1.53	0.00000534	1042
Loss of Function	2.02	3	9.84	0.305	4.27e-7	131

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: Transcriptional activator. Might be involved in the formation of special mesenchymal tissues. {ECO:0000269|PubMed:9169153}.;
Disease: DISEASE: Lymphedema-distichiasis (LYD) [MIM:153400]: A disorder characterized by primary limb lymphedema associated with distichiasis (double rows of eyelashes, with extra eyelashes growing from the Meibomian gland orifices). Swelling of the extremities, due to altered lymphatic flow, usually appears in late childhood or puberty. Most affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia. Drooping of the upper eyelid (ptosis) is a variable feature of the lymphedema-distichiasis syndrome, occurring in about 30% of patients. {ECO:0000269|PubMed:11078474, ECO:0000269|PubMed:11371511, ECO:0000269|PubMed:11499682}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.238

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.928

Gene Damage Prediction

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