Human Gene Module / Chromosome 3 / FOXP1

FOXP1forkhead box P1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
35 / 72
Rare Variants / Common Variants
164 / 3
EAGLE Score
60.45
Strong Learn More
Aliases
FOXP1, QRF1
Associated Syndromes
FOXP1 syndrome
Chromosome Band
3p13
Associated Disorders
DD/NDD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

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). Additional de novo likely gene-disruptive/protein-truncating variants in FOXP1 were identified in ASD probands from the SPARK cohort and the Autism Sequencing Consortium in Feliciano et al., 2019 and Satterstrom et al., 2020, respectively; furthermore, transmission and de novo association (TADA) analysis in both reports identified FOXP1 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified FOXP1 as a gene reaching exome-wide significance (P < 2.5E-06). Assessment of a combined cohort of 22 individuals with pathogenic or likely pathogenic FOXP1 variants consisting of 17 novel individuals and 5 previously reported individuals in Pilar Trelles et al., 2021 found that 5 of the 21 individuals in this cohort for whom psychiatric history was available received a diagnosis of autism spectrum disorder based on expert clinical consensus.

Molecular Function

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

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FOXP1 (72 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 panel 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 schizophrenia 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 2 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
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 Support FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability? Myers A , et al. (2017) No -
34 Recent Recommendation Prospective investigation of FOXP1 syndrome Siper PM , et al. (2017) No ID, ASD or autistic features
35 Support A De Novo FOXP1 Truncating Mutation in a Patient Originally Diagnosed as C Syndrome Urreizti R , et al. (2018) No Autistic features, macrocephaly
36 Recent Recommendation Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders Estruch SB , et al. (2018) No -
37 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
38 Support Whole genome sequencing identifies a de novo 2.1 Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability Vuillaume ML , et al. (2018) No Autistic features
39 Recent Recommendation An Autism-Related, Nonsense Foxp1 Mutant Induces Autophagy and Delays Radial Migration of the Cortical Neurons Li X , et al. (2018) No -
40 Support Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1 Johnson TB , et al. (2018) No -
41 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
42 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
43 Support Targeted Next-Generation Sequencing of Korean Patients With Developmental Delay and/or Intellectual Disability Han JY , et al. (2019) No ASD
44 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders Schluth-Bolard C , et al. (2019) No -
45 Support Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy Jay K , et al. (2019) Yes -
46 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders Gao C , et al. (2019) No Autistic features
47 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
48 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
49 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
50 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
51 Recent recommendation - Garcia-Oscos F et al. (2021) No -
52 Support - Ohashi K et al. (2021) Yes -
53 Support - Braden RO et al. (2021) No ASD, ADHD, ID
54 Support - Lin SZ et al. (2021) Yes -
55 Support - Pode-Shakked B et al. (2021) No ASD, epilepsy/seizures
56 Support - Trelles MP et al. (2021) No ASD
57 Support - Mahjani B et al. (2021) Yes -
58 Support - Wang J et al. (2022) No -
59 Support - Wang J et al. (2022) No -
60 Support - Brea-Fernández AJ et al. (2022) Yes -
61 Support - Hu C et al. (2022) Yes -
62 Support - Zhou X et al. (2022) Yes ADHD
63 Support - Chen M et al. (2022) No Autistic features
64 Support - Chan AJS et al. (2022) Yes ADHD, DD
65 Recent Recommendation - Kundishora AJ et al. (2023) No ASD, DD
66 Support - Miyake N et al. (2023) Yes -
67 Support - Riquin K et al. (2023) Yes -
68 Support - Cesaroni CA et al. (2023) Yes -
69 Support - Park SHE et al. (2023) Yes -
70 Support - et al. () Yes -
71 Support - et al. () No Stereotypy
72 Support - et al. () No ASD
Rare Variants   (164)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
A>C - intron_variant - - - 20848658 Horn D , et al. (2010)
C>T - intron_variant - - - 20848658 Horn D , et al. (2010)
G>A - intron_variant - - - 20848658 Horn D , et al. (2010)
G>T - intron_variant - - - 20848658 Horn D , et al. (2010)
T>C - intron_variant - - - 20848658 Horn D , et al. (2010)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - inversion De novo - - 29969624 Vuillaume ML , et al. (2018)
- - copy_number_loss De novo - - 20848658 Horn D , et al. (2010)
- - inversion De novo - Simplex 37495270 Riquin K et al. (2023)
- - copy_number_loss De novo - - 34109629 Braden RO et al. (2021)
- - copy_number_loss De novo - - 20950788 Hamdan FF , et al. (2010)
- - copy_number_loss De novo - Simplex 34447835 Lin SZ et al. (2021)
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)
- - copy_number_loss De novo - - 28735298 Meerschaut I , et al. (2017)
A>G - intron_variant Familial Maternal - 20848658 Horn D , et al. (2010)
- - inframe_insertion Familial Maternal - 20848658 Horn D , et al. (2010)
- - copy_number_loss De novo - Simplex 23287644 Palumbo O , et al. (2013)
c.1030C>T p.Gln344Ter stop_gained De novo - Simplex 37895307 et al. ()
delTTAAG - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss Familial Paternal - 34109629 Braden RO et al. (2021)
c.511-1G>A - splice_site_variant Unknown - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Unknown Not maternal - 20848658 Horn D , et al. (2010)
c.301A>G p.Met101Val missense_variant - - - 20848658 Horn D , et al. (2010)
c.781T>C p.Ser261Pro missense_variant - - - 20848658 Horn D , et al. (2010)
c.768G>A p.Thr256= synonymous_variant - - - 20848658 Horn D , et al. (2010)
- - copy_number_loss De novo - Simplex 24214399 Le Fevre AK , et al. (2013)
c.1146+1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1781T>G p.Leu594Arg missense_variant - - - 20848658 Horn D , et al. (2010)
c.1627C>T p.Arg543Cys stop_gained De novo - - 31178897 Gao C , et al. (2019)
c.1255C>T p.Gln419Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1489C>T p.Arg497Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.1507C>T p.Arg503Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.975-2A>C - splice_site_variant De novo - - 28884888 Myers A , et al. (2017)
- - copy_number_loss Unknown - Multiplex 23375656 Girirajan S , et al. (2013)
c.109T>C p.Ser37Pro missense_variant Unknown - - 35741772 Hu C et al. (2022)
G>A - 5_prime_UTR_variant Familial Paternal - 20848658 Horn D , et al. (2010)
c.1425+5G>A - splice_site_variant De novo - - 33590427 Ohashi K et al. (2021)
c.1146+1G>A - splice_site_variant Unknown - - 36309498 Chan AJS et al. (2022)
c.975-2A>C - splice_site_variant De novo - - 29090079 Siper PM , et al. (2017)
c.532C>T p.Gln178Ter stop_gained De novo - - 34109629 Braden RO et al. (2021)
c.1146+1G>A - splice_site_variant De novo - - 34109629 Braden RO et al. (2021)
c.1886+5G>T - splice_site_variant De novo - - 34109629 Braden RO et al. (2021)
c.1111G>A p.Val371Met missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.1850G>A p.Ser617Asn missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.107G>A p.Arg36Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1317C>G p.Tyr439Ter stop_gained De novo - - 26647308 Sollis E , et al. (2015)
c.1141C>T p.Gln381Ter stop_gained De novo - - 34109629 Braden RO et al. (2021)
c.1489C>T p.Arg497Ter stop_gained De novo - - 34109629 Braden RO et al. (2021)
c.1649+418G>A - missense_variant De novo - - 30385778 Johnson TB , et al. (2018)
c.1349-4_1353del - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.155C>T p.Ala52Val missense_variant De novo - - 30631761 Han JY , et al. (2019)
c.1573C>T p.Arg525Ter stop_gained De novo - - 20950788 Hamdan FF , et al. (2010)
c.1425+1G>A - splice_site_variant De novo - - 29330474 Urreizti R , et al. (2018)
c.693C>G p.Leu231= stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
c.1409A>G p.Tyr470Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1419A>T p.Leu473Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1541G>A p.Arg514His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1574G>A p.Arg525Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.511-1G>A - splice_site_variant Unknown - - 28735298 Meerschaut I , et al. (2017)
c.974+1G>C - splice_site_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.1349-5_1350del - splice_site_variant De novo - - 28708303 Chrot E , et al. (2017)
c.1317C>G p.Tyr439Ter stop_gained De novo - - 27479843 Lelieveld SH et al. (2016)
c.1429-2A>G - splice_site_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.1570C>T p.Arg524Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.1574G>A p.Arg525Lys missense_variant De novo - - 28884888 Myers A , et al. (2017)
c.940G>A p.Glu314Lys missense_variant De novo - - 28741757 Sollis E , et al. (2017)
c.664G>T p.Gly222Cys missense_variant De novo - - 34109629 Braden RO et al. (2021)
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
c.1573C>T p.Arg525Ter stop_gained De novo - - 27848944 Trujillano D , et al. (2016)
c.1526G>A p.Trp509Ter stop_gained Unknown - - 28735298 Meerschaut I , et al. (2017)
c.1573C>T p.Arg525Ter stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
c.1579G>T p.Glu527Ter stop_gained De novo - - 28735298 Meerschaut I , et al. (2017)
c.1425+5G>A - splice_site_variant De novo - Simplex 36973392 Miyake N et al. (2023)
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.1538G>A p.Arg513His missense_variant De novo - - 28741757 Sollis E , et al. (2017)
c.1409A>G p.Tyr470Cys missense_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.1490G>C p.Arg497Pro missense_variant De novo - - 34109629 Braden RO et al. (2021)
c.1540C>T p.Arg514Cys missense_variant De novo - - 34109629 Braden RO et al. (2021)
c.1541G>A p.Arg514His missense_variant De novo - - 34109629 Braden RO et al. (2021)
c.1438G>A p.Glu480Lys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.643C>A p.Pro215Thr missense_variant Familial - - 20950788 Hamdan FF , et al. (2010)
c.110C>G p.Ser37Cys missense_variant Unknown - Simplex 30564305 Guo H , et al. (2018)
c.1649+434_1649+445del - inframe_deletion De novo - - 29090079 Siper PM , et al. (2017)
c.1240del p.Leu414Ter frameshift_variant Unknown - - 29090079 Siper PM , et al. (2017)
c.*3413_*3414del - 3_prime_UTR_variant De novo - Simplex 31111659 Jay K , et al. (2019)
c.13T>C p.Ser5Pro missense_variant Familial Maternal - 20848658 Horn D , et al. (2010)
c.1507C>T p.Arg503Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1429-1G>T - splice_site_variant De novo - Simplex 37521304 Cesaroni CA et al. (2023)
c.1546C>T p.Arg516Cys missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.2060C>G p.Pro687Arg missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1169C>T p.Thr390Ile missense_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.1543C>G p.His515Asp missense_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.110C>G p.Ser37Cys missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.115G>A p.Gly39Arg 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.1538G>A p.Arg513His missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.1A>G p.Met1? initiator_codon_variant De novo - Simplex 25767709 Song H , et al. (2015)
c.1849G>A p.Ala617Thr missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.643C>G p.Pro215Ala missense_variant Familial Maternal - 20848658 Horn D , et al. (2010)
c.952G>A p.Glu318Lys missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.649C>T p.Gln217Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1649+5G>A - splice_site_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1648G>A p.Gly550Ser splice_site_variant De novo - Simplex 35991577 Chen M et al. (2022)
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.1807G>A p.Ala603Thr missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1188G>A p.Ser396= synonymous_variant Familial Maternal - 20848658 Horn D , et al. (2010)
c.1515C>T p.Asn505= synonymous_variant Familial Maternal - 20848658 Horn D , et al. (2010)
c.307A>G p.Thr103Ala missense_variant Familial Paternal - 33590427 Ohashi K et al. (2021)
c.606del p.Gly203AlafsTer3 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1977C>G p.His659Gln missense_variant Familial Paternal - 33590427 Ohashi K et al. (2021)
c.1354dup p.Ile452AsnfsTer9 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1541G>A p.Arg514His missense_variant De novo - Simplex 31406558 Munnich A , et al. (2019)
c.320T>C p.Ile107Thr missense_variant Unknown - Unknown 24083349 Worthey EA , et al. (2013)
c.1103dup p.His368GlnfsTer93 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1241del p.Leu414ArgfsTer59 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.448del p.Gln150AsnfsTer56 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.229del p.Gln77LysfsTer5 frameshift_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.110C>G p.Ser37Cys missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.155C>T p.Ala52Val missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.980T>C p.Leu327Pro missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
- - copy_number_loss De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1669_1676del p.Asn557GlufsTer19 splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.447dup p.Gln150ThrfsTer20 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1722+1>TGCAGCTTTACAG p.? splice_site_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.1590_1601del p.Gly531_Trp534del inframe_deletion De novo - - 34109629 Braden RO et al. (2021)
c.987_990del p.Glu330MetfsTer21 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1537C>T p.Arg513Cys missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1553G>A p.Ser518Asn missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1240dup p.Leu414ProfsTer46 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1241del p.Leu414ArgfsTer59 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.945_946insT p.Val316CysfsTer15 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1240_1241del p.Leu414AspfsTer45 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1420_1427del p.Ile474GlyfsTer14 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1311_1321del p.Arg438GlnfsTer19 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1574G>A p.Arg525Lys missense_variant Unknown Not paternal - 30385778 Johnson TB , et al. (2018)
c.1355T>G p.Ile452Ser missense_variant Familial Paternal - 31209962 Aspromonte MC , et al. (2019)
c.1707_1719dup p.Ala574CysfsTer9 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.932_936del p.Pro311LeufsTer2 frameshift_variant Unknown - - 28735298 Meerschaut I , et al. (2017)
c.299C>G p.Ala100Gly missense_variant Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.1014dup p.Ala339SerfsTer4 frameshift_variant De novo - Simplex 21572417 O'Roak BJ , et al. (2011)
c.1456_1457insAAAC p.Thr486LysfsTer5 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
- - complex_structural_alteration Familial Maternal Simplex 30923172 Schluth-Bolard C , et al. (2019)
c.450dup p.Gln151ThrfsTer19 frameshift_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.1177_1181dup p.Ala395SerfsTer22 frameshift_variant De novo - Simplex 28344757 Chen R , et al. (2017)
c.1333_1335delinsAA p.Val445AsnfsTer29 frameshift_variant De novo - - 29090079 Siper PM , et al. (2017)
c.1333_1335delinsAA p.Val445AsnfsTer29 frameshift_variant De novo - - 34109629 Braden RO et al. (2021)
c.1465delinsAACAC p.Glu489AsnfsTer5 frameshift_variant De novo - - 28735298 Meerschaut I , et al. (2017)
c.453dup p.Gln152ThrfsTer20 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.573dup p.Gln192ThrfsTer103 frameshift_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1267_1268del p.Val423HisfsTer36 frameshift_variant De novo - Simplex 25853299 Lozano R , et al. (2015)
c.37_40del p.Gly13GlnfsTer14 frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1317_1327del p.Arg440GlnfsTer19 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1366C>T p.Gln456Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1705_1706insTGCAGCTTTACAG p.Asn569MetfsTer14 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1178_1179insAGTCA p.Ser394ValfsTer23 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1169C>T p.Thr390Ile missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.919G>A p.Val307Ile splice_site_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1160_1161insTAAGACGTTGTTTTTTTCCTTGCAGTTGAATCTGGTATCA p.Ser388LysfsTer85 frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
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)
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
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

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."

1/1/2021
1
icon
1

Score remained at 1

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).

Reports Added
[Autism-linked gene FoxP1 selectively regulates the cultural transmission of learned vocalizations2021] [Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings2021]
1/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
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).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorde...2019] [Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019] [Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
4/1/2019
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...2019]
1/1/2019
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018] [Targeted Next-Generation Sequencing of Korean Patients With Developmental Delay and/or Intellectual Disability.2019]
10/1/2018
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?2017] [Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1.2018] [Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[Whole genome sequencing identifies a de novo 2.1Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability.2018] [An Autism-Related, Nonsense Foxp1 Mutant Induces Autophagy and Delays Radial Migration of the Cortical Neurons.2018]
10/1/2017
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[Prospective investigation of FOXP1 syndrome.2017]
7/1/2017
2
icon
2S

Decreased from 2 to 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%).

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017] [FOXP1-related intellectual disability syndrome: a recognisable entity.2017] [Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders.2017] [Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
2
icon
2

Decreased from 2 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).

Reports Added
[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] [3p14.1 de novo microdeletion involving the FOXP1 gene in an adult patient with autism, severe speech delay and deficit of motor coordination.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Increased gene expression of FOXP1 in patients with autism spectrum disorders.2013] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.2013] [FOXP1 mutations cause intellectual disability and a recognizable phenotype.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment.2015] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits.2010] [Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain.2003] [Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction.2004] [A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.2015] [FoxP1 orchestration of ASD-relevant signaling pathways in the striatum.2015] [Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.2017] [SUMOylation of FOXP1 regulates transcriptional repression via CtBP1 to drive dendritic morphogenesis.2017] [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]
1/1/2017
2
icon
2

Decreased from 2 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).

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
10/1/2016
2
icon
2

Decreased from 2 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).

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
7/1/2016
2
icon
2

Decreased from 2 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).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
2
icon
2

Decreased from 2 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).

Reports Added
[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] [3p14.1 de novo microdeletion involving the FOXP1 gene in an adult patient with autism, severe speech delay and deficit of motor coordination.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Increased gene expression of FOXP1 in patients with autism spectrum disorders.2013] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.2013] [FOXP1 mutations cause intellectual disability and a recognizable phenotype.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment.2015] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits.2010] [Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain.2003] [Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction.2004] [A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.2015] [FoxP1 orchestration of ASD-relevant signaling pathways in the striatum.2015] [Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
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).

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment.2015] [A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment.2015]
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).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
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).

Reports Added
[Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
Interactome
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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