Human Gene Module / Chromosome 15 / CYFIP1

CYFIP1cytoplasmic FMR1 interacting protein 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 24
Rare Variants / Common Variants
10 / 5
Aliases
CYFIP1, P140SRA-1,  SHYC,  SRA1
Associated Syndromes
Chromosome 15q11.2 deletion syndrome
Chromosome Band
15q11.2
Associated Disorders
ID
Relevance to Autism

A rare CYFIP1 deletion was found in a patient with PDD-NOS and mild intellectual disability (Leblond et al., 2012).

Molecular Function

Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit is an adapter between EIF4E and FMR1. Promotes the translation repression activity of FMR1 in brain probably by mediating its association with EIF4E and mRNA. Regulates formation of membrane ruffles and lamellipodia. Plays a role in axon outgrowth. Binds to F-actin but not to RNA. Part of the WAVE complex that regulates actin filament reorganization via its interaction with the Arp2/3 complex. Actin remodeling activity is regulated by RAC1. Regulator of epithelial morphogenesis. May act as an invasion suppressor in cancers.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CYFIP1 (24 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P Schenck A , et al. (2001) No -
2 Support A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder van der Zwaag B , et al. (2009) Yes -
3 Primary Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders Leblond CS , et al. (2012) Yes ID
4 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
5 Recent Recommendation CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation De Rubeis S , et al. (2013) No -
6 Positive Association Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders Waltes R , et al. (2014) Yes -
7 Recent Recommendation The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines Pathania M , et al. (2014) No -
8 Recent Recommendation Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity Yoon KJ , et al. (2014) No -
9 Recent Recommendation Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR Oguro-Ando A , et al. (2014) No -
10 Positive Association Common Regulatory Variants of CYFIP1 Contribute to Susceptibility for Autism Spectrum Disorder (ASD) and Classical Autism Wang J , et al. (2015) Yes -
11 Recent Recommendation Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks Nebel RA , et al. (2016) No -
12 Recent Recommendation Cyfip1 Regulates Presynaptic Activity during Development Hsiao K , et al. (2016) No -
13 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder Alvarez-Mora MI , et al. (2016) Yes -
14 Positive Association A Common CYFIP1 Variant at the 15q11.2 Disease Locus Is Associated with Structural Variation at the Language-Related Left Supramarginal Gyrus Woo YJ , et al. (2016) No -
15 Support Cytoplasmic FMRP interacting protein 1/2 (CYFIP1/2) expression analysis in autism Noroozi R , et al. (2018) No -
16 Recent Recommendation Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition Davenport EC , et al. (2019) No -
17 Support Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits Kanellopoulos AK et al. (2020) No -
18 Support - Haan N et al. (2021) Yes -
19 Support - Zhou X et al. (2022) Yes -
20 Support - Busch SE et al. (2023) Yes -
21 Support - Sheridan SD et al. (2023) Yes -
22 Support - Vittoria Mariano et al. (2024) No Autistic features
23 Support - Daniel Cabezas De La Fuente et al. (2024) No ASD, SCZ
24 Support - Josephine E Haddon et al. (2024) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1675-131G>C - intron_variant De novo - - 35982159 Zhou X et al. (2022)
c.1630G>A p.Val544Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2867T>G p.Met956Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3073G>A p.Ala1025Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Paternal Simplex 22346768 Leblond CS , et al. (2012)
- - copy_number_gain Familial Paternal Multi-generational 20029941 van der Zwaag B , et al. (2009)
c.2597G>C p.Arg866Pro missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.1426A>G p.Asn476Asp missense_variant Familial Paternal Multiplex 37704042 Vittoria Mariano et al. (2024)
c.2225C>T p.Pro742Leu missense_variant Familial Maternal Multiplex 37704042 Vittoria Mariano et al. (2024)
c.287C>T p.Ala96Val missense_variant Familial Paternal Multi-generational 26845707 Alvarez-Mora MI , et al. (2016)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-125-4321C>T;c.-6-5059C>T;c.-831C>T;c.-33-5032C>T - intron_variant - - - 26094621 Wang J , et al. (2015)
c.1165G>A;c.2458G>A;c.2542G>A;c.2452G>A p.Gly389Ser;p.Gly820Ser;p.Gly848Ser;p.Gly818Ser missense_variant, splice_site_variant - - - 24442360 Waltes R , et al. (2014)
c.208-177C>T;c.292-177C>T - intron_variant - - - 26094621 Wang J , et al. (2015)
c.569+1113A>G;c.653+1113A>G - intron_variant - - - 26094621 Wang J , et al. (2015)
c.1360-629G>T;c.1444-629G>T - intron_variant - - - 27351196 Woo YJ , et al. (2016)
SFARI Gene score
2

Strong Candidate

CYFIP1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). CYFIP1 interacts with FMRP, the protein encoded by FMR1, the gene responsible for Fragile X syndrome (Schenck et al., 2001). CYFIP1 has also been shown to coordinate mRNA translation and cytoskeleton remodeling to enable proper dendritic spine formation (De Rubeis et al., 2013), to be critical for the maintenance of dendritic complexity and stabilization of mature dendritic spines (Pathania et al., 2014), and to regulate presynaptic activity during development (Hsiao et al., 2016). CYFIP1 has been shown to be upregulated in transformed lymphoblastoid cell lines, as well as in post-mortem brain tissue, from 15q11-q13 duplication patients (Oguro-Ando et al., 2015). Inherited missense variants in the CYFIP1 gene have been observed in ASD probands in two studies (Toma et al., 2014; Alvarez-Mora et al., 2016). Common variants in the CYFIP1 gene have been demonstrated to associate with ASD, as well as with inter-individual variation in surface area across the left supramarginal gyrus, a cortical structure implicated in speech and language (Waltes et al., 2014; Wang et al., 2015; Woo et al., 2016).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2021
2
icon
2

Score remained at 2

Description

CYFIP1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). CYFIP1 interacts with FMRP, the protein encoded by FMR1, the gene responsible for Fragile X syndrome (Schenck et al., 2001). CYFIP1 has also been shown to coordinate mRNA translation and cytoskeleton remodeling to enable proper dendritic spine formation (De Rubeis et al., 2013), to be critical for the maintenance of dendritic complexity and stabilization of mature dendritic spines (Pathania et al., 2014), and to regulate presynaptic activity during development (Hsiao et al., 2016). CYFIP1 has been shown to be upregulated in transformed lymphoblastoid cell lines, as well as in post-mortem brain tissue, from 15q11-q13 duplication patients (Oguro-Ando et al., 2015). Inherited missense variants in the CYFIP1 gene have been observed in ASD probands in two studies (Toma et al., 2014; Alvarez-Mora et al., 2016). Common variants in the CYFIP1 gene have been demonstrated to associate with ASD, as well as with inter-individual variation in surface area across the left supramarginal gyrus, a cortical structure implicated in speech and language (Waltes et al., 2014; Wang et al., 2015; Woo et al., 2016).

Reports Added
[Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms2021]
4/1/2020
2
icon
2

Score remained at 2

Description

CYFIP1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). CYFIP1 interacts with FMRP, the protein encoded by FMR1, the gene responsible for Fragile X syndrome (Schenck et al., 2001). CYFIP1 has also been shown to coordinate mRNA translation and cytoskeleton remodeling to enable proper dendritic spine formation (De Rubeis et al., 2013), to be critical for the maintenance of dendritic complexity and stabilization of mature dendritic spines (Pathania et al., 2014), and to regulate presynaptic activity during development (Hsiao et al., 2016). CYFIP1 has been shown to be upregulated in transformed lymphoblastoid cell lines, as well as in post-mortem brain tissue, from 15q11-q13 duplication patients (Oguro-Ando et al., 2015). Inherited missense variants in the CYFIP1 gene have been observed in ASD probands in two studies (Toma et al., 2014; Alvarez-Mora et al., 2016). Common variants in the CYFIP1 gene have been demonstrated to associate with ASD, as well as with inter-individual variation in surface area across the left supramarginal gyrus, a cortical structure implicated in speech and language (Waltes et al., 2014; Wang et al., 2015; Woo et al., 2016).

Reports Added
[Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

CYFIP1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). CYFIP1 interacts with FMRP, the protein encoded by FMR1, the gene responsible for Fragile X syndrome (Schenck et al., 2001). CYFIP1 has also been shown to coordinate mRNA translation and cytoskeleton remodeling to enable proper dendritic spine formation (De Rubeis et al., 2013), to be critical for the maintenance of dendritic complexity and stabilization of mature dendritic spines (Pathania et al., 2014), and to regulate presynaptic activity during development (Hsiao et al., 2016). CYFIP1 has been shown to be upregulated in transformed lymphoblastoid cell lines, as well as in post-mortem brain tissue, from 15q11-q13 duplication patients (Oguro-Ando et al., 2015). Inherited missense variants in the CYFIP1 gene have been observed in ASD probands in two studies (Toma et al., 2014; Alvarez-Mora et al., 2016). Common variants in the CYFIP1 gene have been demonstrated to associate with ASD, as well as with inter-individual variation in surface area across the left supramarginal gyrus, a cortical structure implicated in speech and language (Waltes et al., 2014; Wang et al., 2015; Woo et al., 2016).

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

Decreased from 3 to 3

Description

CYFIP1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). CYFIP1 interacts with FMRP, the protein encoded by FMR1, the gene responsible for Fragile X syndrome (Schenck et al., 2001). CYFIP1 has also been shown to coordinate mRNA translation and cytoskeleton remodeling to enable proper dendritic spine formation (De Rubeis et al., 2013), to be critical for the maintenance of dendritic complexity and stabilization of mature dendritic spines (Pathania et al., 2014), and to regulate presynaptic activity during development (Hsiao et al., 2016). CYFIP1 has been shown to be upregulated in transformed lymphoblastoid cell lines, as well as in post-mortem brain tissue, from 15q11-q13 duplication patients (Oguro-Ando et al., 2015). Inherited missense variants in the CYFIP1 gene have been observed in ASD probands in two studies (Toma et al., 2014; Alvarez-Mora et al., 2016). Common variants in the CYFIP1 gene have been demonstrated to associate with ASD, as well as with inter-individual variation in surface area across the left supramarginal gyrus, a cortical structure implicated in speech and language (Waltes et al., 2014; Wang et al., 2015; Woo et al., 2016).

Reports Added
[Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition.2019]
10/1/2017
icon
3

Increased from to 3

Description

CYFIP1 is one of four genes that resides within the 15q11.2 CNV locus, a chromosomal region between breakpoints 1 (BP1) and 2 (BP2) of the Prader-Willi/Angelman syndrome critical region in which deletions and duplications are associated with increased susceptibility to neurodevelopmental disorders, including autism (van der Zwaag et al., 2010; Leblond et al., 2012). CYFIP1 interacts with FMRP, the protein encoded by FMR1, the gene responsible for Fragile X syndrome (Schenck et al., 2001). CYFIP1 has also been shown to coordinate mRNA translation and cytoskeleton remodeling to enable proper dendritic spine formation (De Rubeis et al., 2013), to be critical for the maintenance of dendritic complexity and stabilization of mature dendritic spines (Pathania et al., 2014), and to regulate presynaptic activity during development (Hsiao et al., 2016). CYFIP1 has been shown to be upregulated in transformed lymphoblastoid cell lines, as well as in post-mortem brain tissue, from 15q11-q13 duplication patients (Oguro-Ando et al., 2015). Inherited missense variants in the CYFIP1 gene have been observed in ASD probands in two studies (Toma et al., 2014; Alvarez-Mora et al., 2016). Common variants in the CYFIP1 gene have been demonstrated to associate with ASD, as well as with inter-individual variation in surface area across the left supramarginal gyrus, a cortical structure implicated in speech and language (Waltes et al., 2014; Wang et al., 2015; Woo et al., 2016).

Reports Added
[A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-...2001]
Krishnan Probability Score

Score 0.44793090762929

Ranking 11868/25841 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 0.99493303161826

Ranking 1530/18225 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
Sanders TADA Score

Score 0.9470502561912

Ranking 17118/18665 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 11

Ranking 170/461 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 0.15222181055641

Ranking 5125/20870 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
CNVs associated with CYFIP1(1 CNVs)
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15q11.2 122 Deletion-Duplication 161  /  2259
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