Human Gene Module / Chromosome 16 / RBFOX1

RBFOX1RNA binding protein, fox-1 homolog (C. elegans) 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 34
Rare Variants / Common Variants
50 / 2
Aliases
RBFOX1, 2BP1,  A2BP1,  FOX-1,  FOX1,  HRNBP1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
16p13.3
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

Studies have identified variations in the RBFOX1 gene with autism and developmental delay. One study (Sebat et al., 2007) found that de novo CNVs were more significantly identified with autism than had been previously recognized.

Molecular Function

RNA-binding protein that regulates alternative splicing events by binding to 5'-UGCAUGU-3' elements. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis.

Reports related to RBFOX1 (34 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited A novel protein with RNA-binding motifs interacts with ataxin-2. Shibata H , et al. (2000) No -
2 Recent Recommendation Molecular basis of RNA recognition by the human alternative splicing factor Fox-1. Auweter SD , et al. (2005) No -
3 Recent Recommendation Role for Fox-1/Fox-2 in mediating the neuronal pathway of calcitonin/calcitonin gene-related peptide alternative RNA processing. Zhou HL , et al. (2006) No -
4 Primary Strong association of de novo copy number mutations with autism. Sebat J , et al. (2007) Yes -
5 Positive Association Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. Martin CL , et al. (2007) Yes -
6 Recent Recommendation Repression of prespliceosome complex formation at two distinct steps by Fox-1/Fox-2 proteins. Zhou HL and Lou H (2008) No -
7 Recent Recommendation Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Zhang C , et al. (2008) No -
8 Recent Recommendation Alternative isoform regulation in human tissue transcriptomes. Wang ET , et al. (2008) No -
9 Recent Recommendation U1-independent pre-mRNA splicing contributes to the regulation of alternative splicing. Fukumura K , et al. (2009) No -
10 Recent Recommendation A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-... Zhai G , et al. (2009) No -
11 Recent Recommendation An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons. Lee JA , et al. (2009) No -
12 Recent Recommendation Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1). Hammock EA and Levitt P (2011) No -
13 Recent Recommendation The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Gehman LT , et al. (2011) No -
14 Recent Recommendation Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental... Mikhail FM , et al. (2011) No -
15 Recent Recommendation Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis. Davis LK , et al. (2012) Yes -
16 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
17 Recent Recommendation Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD). Pistoni M , et al. (2013) No -
18 Support Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Lal D , et al. (2013) No ASD, DD
19 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
20 Recent Recommendation Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associ... Stambolian D , et al. (2013) No -
21 Support Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations. Zhao WW (2013) No ID, ASD
22 Support RBFOX1 and RBFOX3 mutations in rolandic epilepsy. Lal D , et al. (2013) No -
23 Negative Association Outfoxed by RBFOX1-a caution about ascertainment bias. Kamien B , et al. (2014) Yes -
24 Recent Recommendation RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts. Li YI , et al. (2014) No -
25 Recent Recommendation Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. Hamada N , et al. (2015) No -
26 Recent Recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Turner TN , et al. (2016) Yes -
27 Recent Recommendation MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1. Guven-Ozkan T , et al. (2016) No -
28 Recent Recommendation Rbfox Proteins Regulate Splicing as Part of a Large Multiprotein Complex LASR. Damianov A , et al. (2016) No -
29 Recent Recommendation Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development. Hamada N , et al. (2016) No -
30 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
31 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 -
32 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardias AF , et al. (2018) No -
33 Recent Recommendation Rbfox1 Mediates Cell-type-Specific Splicing in Cortical Interneurons. Wamsley B , et al. (2018) No -
34 Support Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels. Tomassoni-Ardori F , et al. (2019) No -
Rare Variants   (50)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - intron_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss - - - 22031302 Mikhail FM , et al. (2011)
- - copy_number_gain Unknown - Unknown 23822903 Zhao WW (2013)
- - copy_number_loss Unknown - Unknown 23822903 Zhao WW (2013)
- - copy_number_loss De novo NA Unknown 23822903 Zhao WW (2013)
c.-331T>A - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.-332C>A - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.27+15T>C - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.-64+13C>G - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.622+27A>G - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.676+92A>G - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.677-25C>G - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.990+73G>T - intron_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss Unknown - Unknown 23350840 Lal D , et al. (2013)
c.-63-124C>G - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.-63-126A>T - intron_variant - - - 17503474 Martin CL , et al. (2007)
insT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.850-5175G>A - intron_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss Familial Maternal Unknown 23822903 Zhao WW (2013)
- - copy_number_loss Unknown - Multiplex 24039908 Lal D , et al. (2013)
c.28-185339A>G - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.*439G>T - 3_prime_UTR_variant - - - 17503474 Martin CL , et al. (2007)
c.-507G>A - 5_prime_UTR_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo NA Simplex 17363630 Sebat J , et al. (2007)
c.162C>T p.Gly54%3D intron_variant - - - 17503474 Martin CL , et al. (2007)
c.-126-6_-126-4del - intron_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss De novo NA Simplex 17503474 Martin CL , et al. (2007)
c.-16+54949C>G - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.316C>T p.Pro106Ser intron_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss Familial Maternal Simplex 23350840 Lal D , et al. (2013)
c.-127+111651A>G - 5_prime_UTR_variant - - - 17503474 Martin CL , et al. (2007)
c.126G>A p.Thr42%3D synonymous_variant - - - 17503474 Martin CL , et al. (2007)
c.282C>T p.Asp94%3D synonymous_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss Familial Maternal Multiplex 23350840 Lal D , et al. (2013)
- - copy_number_loss Familial Paternal Multiplex 23350840 Lal D , et al. (2013)
c.750C>T p.Arg250%3D synonymous_variant - - - 17503474 Martin CL , et al. (2007)
c.976G>A p.Gly326Ser synonymous_variant - - - 17503474 Martin CL , et al. (2007)
NM_018723.3:c.-15-21delT - intron_variant - - - 17503474 Martin CL , et al. (2007)
c.28-185477_28-185476dup - intron_variant - - - 17503474 Martin CL , et al. (2007)
- - copy_number_loss Familial Maternal Simplex 26749308 Turner TN , et al. (2016)
- - copy_number_loss Familial Paternal Multiplex 22678932 Davis LK , et al. (2012)
- - copy_number_loss Familial Maternal Multiplex 24664471 Kamien B , et al. (2014)
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Extended multiplex 23350840 Lal D , et al. (2013)
- - copy_number_loss Familial Paternal Multi-generational 24664471 Kamien B , et al. (2014)
- - copy_number_gain Familial Paternal Possibly multi-generational 24664471 Kamien B , et al. (2014)
c.683_688del p.Gly228_Pro230delinsAla inframe_deletion Familial Paternal Multiplex 24039908 Lal D , et al. (2013)
c.677-23197_677-23193delinsATCCAGTATCCA - frameshift_variant Familial Maternal Multiplex 24039908 Lal D , et al. (2013)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.915-14878G>A;c.996-14878G>A;c.1125-14878G>A;c.1059-14878G>A;c.1111+811G>A - intron_variant - - - 29483656 Pardias AF , et al. (2018)
c.-63-47998G>C;c.67-47998G>C;c.415-47998G>C;c.46-47998G>C;c.535-47998G>C - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
SFARI Gene score
2

Strong Candidate

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

Score Delta: Score remained at 3

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

10/1/2018
3
icon
3

Decreased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

7/1/2018
4.4 + acc1 + acc2
icon
3

Decreased from 4.4 + acc1 + acc2 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

4/1/2018
3
icon
4.4 + acc1 + acc2

Increased from 3 to 4.4 + acc1 + acc2

Description

3

4/1/2017
3
icon
3

Increased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

Reports Added
[Strong association of de novo copy number mutations with autism.2007] [Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism.2007] [Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Outfoxed by RBFOX1-a caution about ascertainment bias.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations.2013] [Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.2013] [RBFOX1 and RBFOX3 mutations in rolandic epilepsy.2013] [A novel protein with RNA-binding motifs interacts with ataxin-2.2000] [Molecular basis of RNA recognition by the human alternative splicing factor Fox-1.2005] [Role for Fox-1/Fox-2 in mediating the neuronal pathway of calcitonin/calcitonin gene-related peptide alternative RNA processing.2006] [Repression of prespliceosome complex formation at two distinct steps by Fox-1/Fox-2 proteins.2008] [Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2.2008] [Alternative isoform regulation in human tissue transcriptomes.2008] [U1-independent pre-mRNA splicing contributes to the regulation of alternative splicing.2009] [A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-...2009] [An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons.2009] [Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1).2011] [The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain.2011] [Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).2013] [Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associ...2013] [RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts.2014] [Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.2015] [Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.2016] [MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1.2016] [Rbfox Proteins Regulate Splicing as Part of a Large Multiprotein Complex LASR.2016] [Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development.2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.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]
10/1/2016
3
icon
3

Increased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

7/1/2016
3
icon
3

Increased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

4/1/2016
3
icon
3

Increased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

Reports Added
[Strong association of de novo copy number mutations with autism.2007] [Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism.2007] [Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Outfoxed by RBFOX1-a caution about ascertainment bias.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations.2013] [Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.2013] [RBFOX1 and RBFOX3 mutations in rolandic epilepsy.2013] [A novel protein with RNA-binding motifs interacts with ataxin-2.2000] [Molecular basis of RNA recognition by the human alternative splicing factor Fox-1.2005] [Role for Fox-1/Fox-2 in mediating the neuronal pathway of calcitonin/calcitonin gene-related peptide alternative RNA processing.2006] [Repression of prespliceosome complex formation at two distinct steps by Fox-1/Fox-2 proteins.2008] [Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2.2008] [Alternative isoform regulation in human tissue transcriptomes.2008] [U1-independent pre-mRNA splicing contributes to the regulation of alternative splicing.2009] [A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-...2009] [An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons.2009] [Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1).2011] [The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain.2011] [Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).2013] [Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associ...2013] [RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts.2014] [Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.2015] [Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.2016] [MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1.2016] [Rbfox Proteins Regulate Splicing as Part of a Large Multiprotein Complex LASR.2016]
1/1/2016
3
icon
3

Increased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

Reports Added
[Strong association of de novo copy number mutations with autism.2007] [Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism.2007] [Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Outfoxed by RBFOX1-a caution about ascertainment bias.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations.2013] [Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.2013] [RBFOX1 and RBFOX3 mutations in rolandic epilepsy.2013] [A novel protein with RNA-binding motifs interacts with ataxin-2.2000] [Molecular basis of RNA recognition by the human alternative splicing factor Fox-1.2005] [Role for Fox-1/Fox-2 in mediating the neuronal pathway of calcitonin/calcitonin gene-related peptide alternative RNA processing.2006] [Repression of prespliceosome complex formation at two distinct steps by Fox-1/Fox-2 proteins.2008] [Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2.2008] [Alternative isoform regulation in human tissue transcriptomes.2008] [U1-independent pre-mRNA splicing contributes to the regulation of alternative splicing.2009] [A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-...2009] [An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons.2009] [Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1).2011] [The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain.2011] [Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).2013] [Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associ...2013] [RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts.2014] [Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.2015] [Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.2016] [MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1.2016]
7/1/2015
3
icon
3

Increased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

Reports Added
[Strong association of de novo copy number mutations with autism.2007] [Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism.2007] [Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Outfoxed by RBFOX1-a caution about ascertainment bias.2014] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations.2013] [Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.2013] [RBFOX1 and RBFOX3 mutations in rolandic epilepsy.2013] [A novel protein with RNA-binding motifs interacts with ataxin-2.2000] [Molecular basis of RNA recognition by the human alternative splicing factor Fox-1.2005] [Role for Fox-1/Fox-2 in mediating the neuronal pathway of calcitonin/calcitonin gene-related peptide alternative RNA processing.2006] [Repression of prespliceosome complex formation at two distinct steps by Fox-1/Fox-2 proteins.2008] [Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2.2008] [Alternative isoform regulation in human tissue transcriptomes.2008] [U1-independent pre-mRNA splicing contributes to the regulation of alternative splicing.2009] [A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-...2009] [An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons.2009] [Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, A2bp1 (Fox1).2011] [The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain.2011] [Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).2013] [Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associ...2013] [RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts.2014] [Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.2015]
1/1/2015
3
icon
3

Increased from 3 to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

7/1/2014
No data
icon
3

Increased from No data to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

4/1/2014
No data
icon
3

Increased from No data to 3

Description

Two individuals (one with MR and 2nd with epilepsy) observed to have translocations; No similar events observed in 192 controls (Bhalla K, 2004); No evidence for nominal association in IMGSAC families for this regional study; previous linkage result not genome-wide significant (MPL = 2.93) (Barnby G, 2005); De novo translocation with demonstration of altered transcription (Martin CL, 2007); p < 10-4 for bipolar / schizoaffective disorder (although not obviously corrected for large gene issue) (Hamshere ML, 2009); rare variant present in 1/335 but not any of > 2000 controls (Elia J, 2010)

Krishnan Probability Score

Score 0.61232251955041

Ranking 174/25841 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 0.93596101829375

Ranking 2875/18225 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
Sanders TADA Score

Score 0.95077827836544

Ranking 18625/18665 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 0

Ranking 456/461 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 0.50373332575333

Ranking 500/20870 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 RBFOX1(1 CNVs)
16p13.3 52 Deletion-Duplication 79  /  493
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
5730409E04Rik RIKEN cDNA 5730409E04Rik gene Mouse Direct Regulation 230757 Q8BP99
Armt1 acidic residue methyltransferase 1 Mouse Direct Regulation 73419 A6H630
C1qtnf4 C1q and tumor necrosis factor related protein 4 Mouse Direct Regulation 67445 Q8R066
Cacna1d Voltage-dependent L-type calcium channel subunit alpha-1D Mouse RNA Binding 12289 Q99246
CALCA calcitonin-related polypeptide alpha Human RNA Binding 796 P06881
CAPN5 calpain 5 Human RNA Binding 726 O15484
CLIP2 CAP-GLY domain containing linker protein 2 Human RNA Binding 7461 Q9UDT6
CLSTN2 calsyntenin 2 Human RNA Binding 64084 Q9H4D0
Cnih1 cornichon family AMPA receptor auxiliary protein 1 Mouse Direct Regulation 12793 O35372
DLX6-AS1 DLX6 antisense RNA 1 Human RNA Binding 285987 N/A
DMRTB1 DMRT-like family B with proline-rich C-terminal, 1 Human Protein Binding 63948 Q96MA1
ELN elastin Human RNA Binding 2006 P15502
Fam131b family with sequence similarity 131, member B Mouse Direct Regulation 76156 Q3TY60
Fam163b family with sequence similarity 163, member B Mouse Direct Regulation 109349 Q8BUM6
Fpgt fucose-1-phosphate guanylyltransferase Mouse Direct Regulation 75540 G5E8F4
GCA grancalcin, EF-hand calcium binding protein Human Protein Binding 25801 P28676
HNRNP H1 heterogeneous nuclear ribonucleoprotein H1 (H) Human Protein Binding 3187 P31943
Hpca hippocalcin Mouse Direct Regulation 15444 P84075
HSFX1 heat shock transcription factor family, X linked 1 Human Protein Binding 100506164 Q9UBD0
Mcts1 malignant T cell amplified sequence 1 Mouse Direct Regulation 68995 Q9DB27
MFSD1 major facilitator superfamily domain containing 1 Human RNA Binding 64747 C9JS94
Mpv17l Mpv17 transgene, kidney disease mutant-like Mouse Direct Regulation 93734 Q99MS3
MRC2 mannose receptor, C type 2 Human RNA Binding 9902 Q9UBG0
MYL6 myosin, light chain 6, alkali, smooth muscle and non-muscle Human RNA Binding 4637 P60660
Nefm neurofilament, medium polypeptide Mouse Direct Regulation 18040 P08553
Neurod2 neurogenic differentiation 2 Mouse Direct Regulation 18013 Q62414
Npy neuropeptide Y Mouse Direct Regulation 109648 P57774
Pcp4l1 Purkinje cell protein 4-like 1 Mouse Direct Regulation 66425 Q6W8Q3
Pnoc prepronociceptin Mouse Direct Regulation 18155 Q64387
Prrt2 proline-rich transmembrane protein 2 Mouse Direct Regulation 69017 E9PUL5
PTPMT1 protein tyrosine phosphatase, mitochondrial 1 Human RNA Binding 114971 E9PAT8
RBM24 RNA binding motif protein 24 Human Protein Binding 221662 Q9BX46
SFRS6 serine/arginine-rich splicing factor 6 Human RNA Binding 6431 Q13247
Shroom2 shroom family member 2 Mouse Direct Regulation 110380 A2ALU4
Slc4a10 Sodium-driven chloride bicarbonate exchanger Mouse RNA Binding 94229 Q5DTL9
Snx16 sorting nexin 16 Mouse Direct Regulation 74718 Q8C080
ST13 suppression of tumorigenicity 13 (colon carcinoma) (Hsp70 interacting protein) Human RNA Binding 6767 P50502
Stac2 SH3 and cysteine rich domain 2 Mouse Direct Regulation 217154 Q8R1B0
TIMP2 TIMP metallopeptidase inhibitor 2 Human RNA Binding 7077 P16035
Tmem179 transmembrane protein 179 Mouse Direct Regulation 104885 Q8BHH9
Vamp1 vesicle-associated membrane protein 1 Mouse Direct Regulation 22317 Q62442
Vsnl1 visinin-like 1 Mouse Direct Regulation 26950 P62761
xol-1 XO lethal protein 1 Worm RNA Binding 181061 Q23229
Zbtb18 zinc finger and BTB domain containing 18 Mouse Direct Regulation 30928 Q9WUK6
Zfp239 zinc finger protein 239 Mouse Direct Regulation 22685 P24399
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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