Human Gene Module / Chromosome 3 / FOXP1

FOXP1forkhead box P1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
15 / 28
Rare Variants / Common Variants
61 / 2
Aliases
FOXP1, QRF1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association, Functional
Chromosome Band
3p13
Associated Disorders
ID, DD/NDD, ASD
Relevance to Autism

Studies have found that rare mutations in the FOXP1 gene are associated with autism (O'Roak et al., 2011) as well as with intellectual disability and mental retardation (Hamdan et al., 2010; Horn et al., 2010).

Molecular Function

Transcriptional repressor. Plays an important role in the specification and differentiation of lung epithelium.

Reports related to FOXP1 (28 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. Ferland RJ , et al. (2003) No -
2 Highly Cited Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. Teramitsu I , et al. (2004) No -
3 Recent Recommendation Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. Horn D , et al. (2010) No -
4 Support De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Hamdan FF , et al. (2010) Yes ID
5 Primary Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O'Roak BJ , et al. (2011) Yes -
6 Support 3p14.1 de novo microdeletion involving the FOXP1 gene in an adult patient with autism, severe speech delay and deficit of motor coordination. Palumbo O , et al. (2013) Yes -
7 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
8 Support Increased gene expression of FOXP1 in patients with autism spectrum disorders. Chien WH , et al. (2013) Yes -
9 Support Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech. Worthey EA , et al. (2013) No -
10 Support FOXP1 mutations cause intellectual disability and a recognizable phenotype. Le Fevre AK , et al. (2013) No -
11 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ... Brett M , et al. (2014) Yes MCA
12 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
13 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
14 Support A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment. Song H , et al. (2015) No Speech delay
15 Recent Recommendation A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment. Lozano R , et al. (2015) Yes Macrocephaly
16 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
17 Recent recommendation FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. Araujo DJ , et al. (2015) No -
18 Support Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder. Sollis E , et al. (2015) No Autistic features, PDD-NOS
19 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
20 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
21 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
22 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
23 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No Macrocephaly, megalencephaly
24 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
25 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
26 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism. Chen R , et al. (2017) Yes -
27 Recent recommendation SUMOylation of FOXP1 regulates transcriptional repression via CtBP1 to drive dendritic morphogenesis. Rocca DL , et al. (2017) No -
28 Positive association Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ... Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
Rare Variants   (61)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown Not maternal - 20848658 Horn D , et al. (2010)
- - copy_number_loss De novo - - 20848658 Horn D , et al. (2010)
- - copy_number_loss De novo - - 20848658 Horn D , et al. (2010)
c.13T>C p.Ser5Pro missense_variant Familial Maternal - 20848658 Horn D , et al. (2010)
N/A N/A inframe_insertion Familial Maternal - 20848658 Horn D , et al. (2010)
c.301A>G p.Met101Val missense_variant - - - 20848658 Horn D , et al. (2010)
c.643C>G p.Pro215Ala missense_variant Familial Maternal - 20848658 Horn D , et al. (2010)
c.781T>C p.Ser261Pro missense_variant - - - 20848658 Horn D , et al. (2010)
c.1168A>T p.Thr390Ser missense_variant Familial Maternal - 20848658 Horn D , et al. (2010)
c.1709A>G p.Asn570Ser missense_variant Familial Paternal - 20848658 Horn D , et al. (2010)
c.1790A>C p.Asn597Thr missense_variant - - - 20848658 Horn D , et al. (2010)
c.768G>A p.(=) synonymous_variant - - - 20848658 Horn D , et al. (2010)
c.1188G>A p.(=) synonymous_variant Familial Maternal - 20848658 Horn D , et al. (2010)
c.1515C>T p.(=) synonymous_variant Familial Maternal - 20848658 Horn D , et al. (2010)
G to A - 5_prime_UTR_variant Familial Paternal - 20848658 Horn D , et al. (2010)
T to C N/A intron_variant - - - 20848658 Horn D , et al. (2010)
G to A N/A intron_variant - - - 20848658 Horn D , et al. (2010)
C to T N/A intron_variant - - - 20848658 Horn D , et al. (2010)
A to G N/A intron_variant Familial Maternal - 20848658 Horn D , et al. (2010)
C to T N/A intron_variant - - - 20848658 Horn D , et al. (2010)
A to G N/A intron_variant Familial Maternal - 20848658 Horn D , et al. (2010)
A to C N/A intron_variant - - - 20848658 Horn D , et al. (2010)
G to T N/A intron_variant - - - 20848658 Horn D , et al. (2010)
- - copy_number_loss De novo - - 20950788 Hamdan FF , et al. (2010)
c.1573C>T p.Arg525Ter stop_gained De novo - - 20950788 Hamdan FF , et al. (2010)
c.643C>A p.Pro215Ala missense_variant Familial - - 20950788 Hamdan FF , et al. (2010)
c.1014_1015insA p.Ala339SerfsTer4 frameshift_variant De novo - Simplex 21572417 O'Roak BJ , et al. (2011)
- - copy_number_loss De novo - Simplex 23287644 Palumbo O , et al. (2013)
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Unknown - Multiplex 23375656 Girirajan S , et al. (2013)
c.320T>C p.Ile107Thr missense_variant Unknown - Unknown 24083349 Worthey EA , et al. (2013)
- - copy_number_loss De novo - Simplex 24214399 Le Fevre AK , et al. (2013)
c.299C>G p.Ala100Gly missense_variant Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.1507C>T p.Arg503Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
- - copy_number_loss De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.918+1G>A - splice_site_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1366C>T p.Gln456Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1169C>T p.Pro390Leu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1A>G p.Met1Val initiator_codon_variant De novo - Simplex 25767709 Song H , et al. (2015)
c.1267_1268delGT p.Val423HisfsTer37 frameshift_variant De novo - Simplex 25853299 Lozano R , et al. (2015)
c.1393A>G p.Arg465Gly missense_variant De novo - - 26647308 Sollis E , et al. (2015)
c.1540C>T p.Arg514Cys missense_variant De novo - - 26647308 Sollis E , et al. (2015)
c.1317C>G p.Tyr439Ter stop_gained De novo - - 26647308 Sollis E , et al. (2015)
c.1546C>T p.Arg516Cys missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1317C>G p.Tyr439Ter stop_gained De novo - - 27479843 Lelieveld SH , et al. (2016)
delTTAAG - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
C>G - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
C>T - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
T>A - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.125C>T p.Pro42Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.125C>T p.Pro42Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1807G>A p.Glu603Lys missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.115G>A p.Gly39Arg missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.952G>A p.Glu318Lys missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.110C>G p.Ser37Cys missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.1573C>T p.Arg525Ter stop_gained De novo - - 27848944 Trujillano D , et al. (2016)
c.450dup p.Gln151ThrfsTer19 frameshift_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.1757_1770delATGCAGCTTTACAGinsATGCAGCTTTACAGTGCAGCTTTACAG p.Ala591CysfsTer9 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1295C>T;c.1367C>T;c.1592C>T;c.1595C>T;c.1601C>T p.Ala432Val;p.Ala456Val;p.Ala531Val;p.Ala532Val;p.Ala534Val missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
insGACTT - frameshift_variant De novo - Simplex 28344757 Chen R , et al. (2017)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-297-28639G>A;c.-298+21230G>A;c.-202-28639G>A - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
c.1527+1396G>A;c.1530+1396G>A;c.1302+1396G>A;c.1230+1396G>A;c.1536+1396G>A;c.1533+1396G>A;c.1308+139 - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
SFARI Gene score
2

Strong Candidate

A rare de novo loss-of-function (LoF) variant in the FOXP1 gene was first identified in a male patient with autism and non-syndromic ID (PMID 20950788), while additional de novo LoF variants in FOXP1 have been identified in ASD probands from the Simons Simplex Collection (PMIDs 21572417 and 25636768). A fourth ASD-associated de novo LoF variant in FOXP1 was recently identified in a female patient with a history of ASD, mild intellectual disability, and severe speech and language impairment (PMID 25853299). Variants in FOXP1 have also been identified in patients presenting with intellectual disability and significant speech and language deficits (PMID 20848658).

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

04-01-2017
2

Initial score established: 2

Description

A rare de novo loss-of-function (LoF) variant in the FOXP1 gene was first identified in a male patient with autism and non-syndromic ID (PMID 20950788), while additional de novo LoF variants in FOXP1 have been identified in ASD probands from the Simons Simplex Collection (PMIDs 21572417 and 25636768). A fourth ASD-associated de novo LoF variant in FOXP1 was recently identified in a female patient with a history of ASD, mild intellectual disability, and severe speech and language impairment (PMID 25853299). Variants in FOXP1 have also been identified in patients presenting with intellectual disability and significant speech and language deficits (PMID 20848658).

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder.2014] [FoxP1 orchestration of ASD-relevant signaling pathways in the striatum.2015] [Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction.2004] [Increased gene expression of FOXP1 in patients with autism spectrum disorders.2013] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.2013] [3p14.1 de novo microdeletion involving the FOXP1 gene in an adult patient with autism, severe speech delay and deficit of motor coordination.2013] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits.2010] [SUMOylation of FOXP1 regulates transcriptional repression via CtBP1 to drive dendritic morphogenesis.2017] [De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.2010] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.2015] [FOXP1 mutations cause intellectual disability and a recognizable phenotype.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain.2003] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.2017] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment.2015] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.2015] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017]
CNVs associated with FOXP1(1 CNVs)
3p13 9 Deletion 12  /  18
Animal Models associated with FOXP1(6 Models)
FOXP1_1_CKO_HM Genetic
FOXP1_1_KO_HM Genetic
FOXP1_2_CKO_HT Genetic
FOXP1_3_KO_HT Genetic
FOXP1_4_KO_HT Genetic
FOXP1_5_KO_HT Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
4-Oct POU class 5 homeobox 1 Human DNA Binding 5460 Q01860
ADGRL4 adhesion G protein-coupled receptor L4 Human Direct Regulation 64123 Q9HBW9
B3GALT2 UDP-Gal:betaGlcNAc beta 1,3-galactosyltransferase 2 Human Direct Regulation 8707 O43825
BIK BCL2-interacting killer (apoptosis-inducing) Human DNA Binding 638 Q13323
CBLN4 cerebellin 4 precursor Human Direct Regulation 140689 Q9NTU7
CHAC2 ChaC, cation transport regulator homolog 2 (E. coli) Human Direct Regulation 494143 Q8WUX2
CNTN6 contactin 6 Human Direct Regulation 27255 Q9UQ52
CRH corticotropin releasing hormone Human Direct Regulation 1392 P06850
ECE1 PSD3 Human Direct Regulation 1889 P42892
EDN3 endothelin 3 Human Direct Regulation 1908 P14138
Erag Human DNA Binding
FAM81A family with sequence similarity 81 member A Human Direct Regulation 145773 Q8TBF8
FOXP3 Forkhead box protein P3 Human Protein Binding 50943 Q9BZS1
GABRB2 Gamma-aminobutyric acid receptor subunit beta-2 Human Direct Regulation 2561 P47870
GALNT18 polypeptide N-acetylgalactosaminyltransferase 18 Human Direct Regulation 374378 Q6P9A2
GDF3 growth differentiation factor 3 Human DNA Binding 9573 Q9NR23
Gm5631 solute carrier family 22, member 28 Mouse DNA Binding 434674 B2RT89
GRM7 glutamate receptor, metabotropic 7 Human Direct Regulation 2917 Q14831
GYG2 glycogenin 2 Human Direct Regulation 8908 O15488
H13 histocompatibility 13 Mouse DNA Binding 14950 Q9D8V0
IGFBP7 insulin-like growth factor binding protein 7 Human Direct Regulation 3490 Q16270
IL3RA interleukin 3 receptor, alpha (low affinity) Human Protein Binding 3563 P26951
KCNJ2 potassium channel, inwardly rectifying subfamily J, member 2 Human Direct Regulation 3759 P63252
KIAA1984 Coiled-coil domain-containing protein 183 Human Protein Binding 84960 Q5T5S1-2
Mcts2 malignant T cell amplified sequence 2 Mouse DNA Binding 66405 Q9CQ21
MGST1 microsomal glutathione S-transferase 1 Human Direct Regulation 4257 P10620
MIAT myocardial infarction associated transcript (non-protein coding) Human Direct Regulation 440823
MIR1-1 microRNA 1-1 Human RNA Binding 406904 N/A
MIR9 microRNA mir-9-1 Chicken RNA Binding 777892 N/A
MYOF myoferlin Human Direct Regulation 26509 Q9NZM1
NR5A2 nuclear receptor subfamily 5, group A, member 2 Human DNA Binding 2494 B4E2P3
PACRG PARK2 co-regulated Human Direct Regulation 135138 Q96M98
Pcsk2 proprotein convertase subtilisin/kexin type 2 Mouse DNA Binding 18549 P21661
PITX3 paired-like homeodomain transcription factor 3 Mouse DNA Binding 18742 O35160
Rpl36a ribosomal protein L36A-like Mouse DNA Binding 66483 P83882
Rxfp1 relaxin/insulin-like family peptide receptor 1 Mouse DNA Binding 381489 Q6R6I7
SHISA9 shisa family member 9 Human Direct Regulation 729993 B4DS77
SMOC2 SPARC related modular calcium binding 2 Human Direct Regulation 64094 Q9H3U7
TENM1 teneurin transmembrane protein 1 Human Direct Regulation 10178 Q9UKZ4
TENM2 teneurin transmembrane protein 2 Human Direct Regulation 57451 Q9NT68
Tmem125 transmembrane protein 125 Mouse DNA Binding 230678 Q8CHQ6
Wdr65 WD repeat domain 65 Mouse DNA Binding 68625 Q9D180
XYLT1 xylosyltransferase I Human Direct Regulation 64131 Q86Y38
ZIC3 Zic family member 3 Human Direct Regulation 7547 O60481
ZNF385D zinc finger protein 385D Human Direct Regulation 79750 Q9H6B1
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