FOXP2

protein-coding

forkhead box P2, the group of MicroRNA protein coding host genes|Forkhead boxes

Gene summary

This gene encodes a member of the forkhead/winged-helix (FOX) family of transcription factors. It is expressed in fetal and adult brain as well as in several other organs such as the lung and gut. The protein product contains a FOX DNA-binding domain and a large polyglutamine tract and is an evolutionarily conserved transcription factor, which may bind directly to approximately 300 to 400 gene promoters in the human genome to regulate the expression of a variety of genes. This gene is required for proper development of speech and language regions of the brain during embryogenesis, and may be involved in a variety of biological pathways and cascades that may ultimately influence language development. Mutations in this gene cause speech-language disorder 1 (SPCH1), also known as autosomal dominant speech and language disorder with orofacial dyspraxia. Multiple alternative transcripts encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

Previous symbols:

TNRC10
SPCH1

MANE transcript

NM_014491.4

Inheritance

ClinVar variants

P:66U:153B:75

Top phenotype

Speech-language disorder 1

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr7:114,086,327-114,693,772

External References & Databases

Ensembl (ENSG00000128573)

Transcript & Mutation Effects

hg38 • Region Span ~607.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

childhood apraxia of speechSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011184

Submitter: G2P

childhood apraxia of speechSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011184

Submitter: PanelApp Australia

childhood apraxia of speechSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011184

Submitter: Labcorp Genetics (formerly Invitae)

childhood apraxia of speechSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011184

Submitter: Orphanet

specific language disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016226

Submitter: ClinGen

*FOXP2* was first reported in relation to autosomal dominant specific language disorder in 2001 (Lai et al., PMID: 11586359). Nine variants (missense, nonsense, frameshift and a large deletion) that have been reported in 11 probands in 4 publications (PMIDs: 11586359, 15877281, 23918746, 27572252) are included in this curation. A heterozygous *de novo* 14 kb deletion of *FOXP2* exons 12-17 (Reuter et al., 2016; PMID: 27572252) could not be entered into the Gene Curation Interface, and would add an additional 2 points, so the maximum score for genetic evidence (12 points) has been reached. More evidence is available in the literature. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by animal models and *in vitro* functional assays. In summary, there is definitive evidence supporting the relationship between *FOXP2* and autosomal dominant specific language disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panel on May 21, 2019 (SOP Version 6).

Clinical Genomic Database (CGD)

Speech-language disorder 1AD

Manifestation: Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Paternal deletions are associated with Russell-Silver syndrome, and may be related to speech-language involvement in the condition

Refs: 3265313; 11586359; 15326624; 15877281; 17033973; 16470794; 20301499; 22106036; 22105961; 22144704

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXP2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 182

Inborn genetic diseasesTotal: 101

Childhood apraxia of speechTotal: 89

not specifiedTotal: 33

FOXP2-related disorderTotal: 29

Lung adenocarcinomaTotal: 3

Intellectual disabilityTotal: 3

See casesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014491.4. 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			9 clinvar	46 clinvar	3 clinvar	58
missense		7 clinvar	137 clinvar	22 clinvar	2 clinvar	168
nonsense	19 clinvar	11 clinvar				30
start loss	1 clinvar	1 clinvar	1 clinvar			3
frameshift	14 clinvar	8 clinvar	3 clinvar			25
splice donor/acceptor (+/-2bp)	4 clinvar	1 clinvar	3 clinvar	2 clinvar		10
Total	38	28	153	70	5	294

Highest pathogenic variant AF is 0.000006577649

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014491.4	RefSeq	NP_055306.1	16	MANE Select
ENST00000350908.9	Ensembl	ENSP00000265436.7	16	MANE Select
NM_001172766.3	RefSeq	NP_001166237.1	16	Standard
NM_001172767.2	RefSeq	NP_001166238.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxp2	Danio rerio	Structure: central nervous system development Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

foxp2

Danio rerio

Structure: central nervous system development

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pathways Affected in Adenoid Cystic Carcinoma

Biological Process

negative regulation of transcription by RNA polymerase II
positive regulation of mesenchymal cell proliferation
skeletal muscle tissue development
post-embryonic development
cerebellum development

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000408937
Coding exons: 17
Length: 607446
Individuals with no LoFs: 125697
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125709
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.90	276	380	0.726	0.0000195	4865
Missense (PolyPhen)		31	60.052	0.51622		768
Synonymous	-0.986	153	138	1.11	0.00000724	1358
Loss of Function	6.06	6	54.1	0.111	0.00000295	524

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00043	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional repressor that may play a role in the specification and differentiation of lung epithelium. May also play a role in developing neural, gastrointestinal and cardiovascular tissues. Can act with CTBP1 to synergistically repress transcription but CTPBP1 is not essential. Plays a role in synapse formation by regulating SRPX2 levels. Involved in neural mechanisms mediating the development of speech and language.;
Disease: DISEASE: Speech-language disorder 1 (SPCH1) [MIM:602081]: A disorder characterized by severe orofacial dyspraxia resulting in largely incomprehensible speech. Affected individuals have severe impairment in the selection and sequencing of fine orofacial movements which are necessary for articulation, and deficits in several facets of grammatical skills and language processing, such as the ability to break up words into their constituent phonemes. {ECO:0000269|PubMed:11586359}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving FOXP2 is a cause of severe speech and language impairment. Translocation t(5;7)(q22;q31.2).;

Recessive Scores

pRec: 0.651

Intolerance Scores

LoFtool: 0.117
RVIS EVS: -0.82
RVIS percentile EVS: 11.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.968

Gene Damage Prediction

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