Human Gene Module / Chromosome 3 / FOXP1

FOXP1forkhead box P1

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
16 / 36
Rare Variants / Common Variants
98 / 3
Aliases
FOXP1, QRF1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, 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 (36 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 -
29 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No Macrocephaly
30 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
31 Recent recommendation FOXP1-related intellectual disability syndrome: a recognisable entity. Meerschaut I , et al. (2017) No Autistic features (14/20 cases)
32 Support Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders. Sollis E , et al. (2017) No Speech delay, motor delay, repetitive behaviors
33 Recent recommendation Prospective investigation of FOXP1 syndrome. Siper PM , et al. (2017) No ID, ASD or autistic features
34 Support A De Novo FOXP1 Truncating Mutation in a Patient Originally Diagnosed as C Syndrome. Urreizti R , et al. (2018) No Autistic features, macrocephaly
35 Recent recommendation Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders. Estruch SB , et al. (2018) No -
36 Positive association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardias AF , et al. (2018) No -
Rare Variants   (98)
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)
c.1349-5_1350del p.? splice_site_variant De novo - - 28708303 Chrot E , et al. (2017)
C>T p.Arg516His missense_variant De novo - - 28714951 Lim ET , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
c.1573C>T p.Arg525Ter stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
c.1526G>A p.Trp509Ter stop_gained Unknown - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
c.858delC p.Pro286fsTer38 frameshift_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.1543C>G p.His515Asp missense_variant De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
c.1573C>T p.Arg525Ter stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
c.974+1G>C p.? splice_site_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.1579G>T p.Glu527Ter stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
c.1169C>T p.Thr390Ile missense_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.1468delCinsAACAC p.Leu490AsnfsTer4 frameshift_variant De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
c.1429-2A>G p.? splice_site_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.1556_1560delTTCAC p.Leu519GlnfsTer12 frameshift_variant Unknown - - 28735298 Meerschaut I , et al. (2017)
c.511-1G>A p.? splice_site_variant Unknown - - 28735298 Meerschaut I , et al. (2017)
c.1573C>T p.Arg525Ter stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
c.1319C>G p.Ser440Ter stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
c.1541G>A p.Arg514His missense_variant De novo - - 28741757 Sollis E , et al. (2017)
c.1541G>A p.Arg514His missense_variant De novo - - 28741757 Sollis E , et al. (2017)
c.1541G>A p.Arg514His missense_variant De novo - - 28741757 Sollis E , et al. (2017)
c.975-2A>C p.Lys325AsnfsTer12 splice_site_variant De novo - - 29090079 Siper PM , et al. (2017)
c.1333_1335delinsAA p.Val445AsnfsTer29 frameshift_variant De novo - - 29090079 Siper PM , et al. (2017)
c.1506C>G p.Phe502Leu missense_variant De novo - - 29090079 Siper PM , et al. (2017)
c.1240delC p.Leu414Ter frameshift_variant Unknown - - 29090079 Siper PM , et al. (2017)
c.1409A>G p.Tyr470Cys missense_variant De novo - - 29090079 Siper PM , et al. (2017)
c.1590_1601delAGGGGCAGTATG p.Gly531_Trp534del inframe_deletion De novo - - 29090079 Siper PM , et al. (2017)
c.1428+1G>A p.Ala450GlyfsTer13 splice_site_variant De novo - - 29330474 Urreizti R , et al. (2018)
Common Variants   (3)
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)
c.-297-1052C>A;c.-202-1052C>A - intron_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Score remained at 2.1 + S

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2017
2S
icon
2S

Score remained at 2S

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). Assessment of the clinical features observed in 25 novel and 23 previously reported patients with FOXP1 mutations in Meerschaut et al., 2017 demonstrated that autistic features were observed in 24 of 32 cases (75%). Phenotypic characterization, including gold standard ASD testing, of six novel cases and three previously reported cases with FOXP1 variants in Siper et al., 2017 demonstrated that all nine individuals presented with symptoms of ASD (with two receiving a diagnosis of ASD); other frequently observed phenotypes included intellectual disability (7/9 cases), hypotonia (8/9 cases), dysarthria (9/9 cases), and fine/gross motor coordination deficits (9/9 cases).

7/1/2017
2
icon
2S

Score remained at 2S

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). Assessment of the clinical features observed in 25 novel and 23 previously reported patients with FOXP1 mutations in Meerschaut et al., 2017 demonstrated that autistic features were observed in 24 of 32 cases (75%).

4/1/2017
2
icon
2

Score remained at 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]
1/1/2017
2
icon
2

Score remained at 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).

10/1/2016
2
icon
2

Score remained at 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).

7/1/2016
2
icon
2

Score remained at 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).

1/1/2016
2
icon
2

Score remained at 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
[A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.2015] [Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.2015] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.2010] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain.2003] [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] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [FoxP1 orchestration of ASD-relevant signaling pathways in the striatum.2015] [A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment.2015] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.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] [Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction.2004] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits.2010] [FOXP1 mutations cause intellectual disability and a recognizable phenotype.2013] [Increased gene expression of FOXP1 in patients with autism spectrum disorders.2013]
4/1/2015
3
icon
2

Decreased from 3 to 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).

1/1/2015
3
icon
3

Decreased from 3 to 3

Description

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). A second de novo LoF variant in the FOXP1 gene was recently identified in an ASD proband from the Simons Simplex Collection (PMID 25363768).

7/1/2014
No data
icon
3

Increased from No data to 3

Description

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).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

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).

Krishnan Probability Score

Score 0.56835766191383

Ranking 1117/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99975073505513

Ranking 806/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.994

Ranking 18/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.042434425127429

Ranking 43/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 7.5

Ranking 239/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.54069087660197

Ranking 284/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with FOXP1(1 CNVs)
3p13 10 Deletion 13  /  23
Animal Models associated with FOXP1(6 Models)
FOXP1_1_CKO_HM 1 Genetic Mus musculus
FOXP1_1_KO_HM 1 Genetic Mus musculus
FOXP1_2_CKO_HT 1 Genetic Mus musculus
FOXP1_3_KO_HT 1 Genetic Mus musculus
FOXP1_4_KO_HT 1 Genetic Mus musculus
FOXP1_5_KO_HT 1 Genetic Mus musculus
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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