Human Gene Module / Chromosome X / ARHGEF9

ARHGEF9Cdc42 guanine nucleotide exchange factor (GEF) 9

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
9 / 20
Rare Variants / Common Variants
42 / 0
EAGLE Score
14.2
Strong Learn More
Aliases
ARHGEF9, COLLYBISTIN,  EIEE8,  HPEM-2,  PEM-2,  PEM2
Associated Syndromes
-
Chromosome Band
Xq11.1-q11.2
Associated Disorders
ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions (Machado et al., 2016). A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Molecular Function

The protein encoded by this gene is a Rho-like GTPase that acts as a guanine nucleotide exchange factor (GEF) for CDC42 and other genes and promotes the formation of GPHN clusters. Variants in this gene are associated with a form of early infantile epileptic encephalopathy (EIEE8, OMIM 300607).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ARHGEF9 (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering Harvey K , et al. (2004) No Hyperekplexia
2 Primary Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism Machado CO , et al. (2015) Yes -
3 Support Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism Long P , et al. (2016) No -
4 Support Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder Bhat G , et al. (2016) Yes -
5 Recent Recommendation ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation Alber M , et al. (2017) No Autistic features
6 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
7 Support ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation Wang JY , et al. (2017) No -
8 Support Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation Aarabi M , et al. (2018) Yes -
9 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID, epilepsy/seizures
10 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
11 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) No -
12 Support - Mahjani B et al. (2021) Yes -
13 Support - Chen S et al. (2021) Yes Epilepsy/seizures
14 Support - Qiu T et al. (2021) No -
15 Support - Hines DJ et al. (2022) Yes ADHD
16 Support - Yang H et al. (2022) No -
17 Support - Zhou X et al. (2022) Yes -
18 Support - Erica Rosina et al. (2024) No -
19 Support - Ruohao Wu et al. (2024) Yes -
20 Support - Wanqi Wang et al. (2024) No -
Rare Variants   (42)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion De novo - - 28589176 Alber M , et al. (2017)
- - translocation De novo - - 28589176 Alber M , et al. (2017)
- - copy_number_loss De novo - - 27238888 Bhat G , et al. (2016)
- - copy_number_loss De novo - - 28589176 Alber M , et al. (2017)
- - copy_number_loss De novo - - 30048823 Aarabi M , et al. (2018)
- - copy_number_loss De novo - Simplex 25898924 Machado CO , et al. (2015)
c.138G>A p.Trp46Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.925-1G>T - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.741C>A p.Cys247Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1370-2A>G - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.194G>A p.Trp65Ter stop_gained De novo - - 35169261 Hines DJ et al. (2022)
c.1141+2T>C - splice_site_variant De novo - - 28589176 Alber M , et al. (2017)
c.940C>T p.Gln314Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.188G>A p.Arg63Lys missense_variant De novo - - 35638461 Yang H et al. (2022)
c.311G>A p.Arg104Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.924G>T p.Glu308Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1094G>A p.Arg365His missense_variant De novo - - 35638461 Yang H et al. (2022)
c.682C>T p.Gln228Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.4C>T p.Gln2Ter stop_gained Familial Maternal - 28589176 Alber M , et al. (2017)
c.311G>A p.Arg104Gln missense_variant De novo - - 28589176 Alber M , et al. (2017)
c.530T>C p.Leu177Pro missense_variant De novo - - 28589176 Alber M , et al. (2017)
c.164G>C p.Gly55Ala missense_variant De novo - - 15215304 Harvey K , et al. (2004)
c.1198G>A p.Glu400Lys missense_variant De novo - - 28589176 Alber M , et al. (2017)
c.417G>A p.Gln139%3D stop_gained Familial Maternal - 34800434 Chen S et al. (2021)
c.510T>A p.Tyr170Ter stop_gained Familial Maternal - 34800434 Chen S et al. (2021)
c.865C>T p.Arg289Ter stop_gained Familial Paternal - 28708303 Chrot E , et al. (2017)
c.417G>A p.Met139Ile stop_gained Familial Maternal - 31031587 Xiong J , et al. (2019)
c.510T>A p.Tyr170Ter stop_gained Familial Maternal - 31031587 Xiong J , et al. (2019)
c.639C>G p.Asn213Lys missense_variant Familial Maternal - 35638461 Yang H et al. (2022)
c.1094G>A p.Arg365His missense_variant Familial Maternal - 35638461 Yang H et al. (2022)
c.1162A>G p.Met388Val missense_variant Familial Maternal - 35638461 Yang H et al. (2022)
c.869G>A p.Arg290His missense_variant De novo - Multiplex 28589176 Alber M , et al. (2017)
c.1067G>A p.Arg356Gln missense_variant Familial Maternal - 28589176 Alber M , et al. (2017)
c.1105del p.Glu369LysfsTer26 frameshift_variant De novo - - 35169261 Hines DJ et al. (2022)
c.950C>T p.Ser317Leu missense_variant Familial Maternal - 31231135 Bruel AL , et al. (2019)
c.477_490del p.Met159IlefsTer6 frameshift_variant De novo - Simplex 34851771 Qiu T et al. (2021)
c.331C>T p.Arg111Trp missense_variant Familial Maternal Simplex 38764027 Ruohao Wu et al. (2024)
c.950C>G p.Ser317Trp missense_variant Familial Maternal Multiplex 28589176 Alber M , et al. (2017)
c.868C>T p.Arg290Cys missense_variant Familial Maternal Multiplex 29130122 Wang JY , et al. (2017)
c.347G>A p.Arg116His missense_variant Familial Maternal Simplex 38041506 Erica Rosina et al. (2024)
c.1012C>T p.Arg338Trp missense_variant Familial Maternal Multi-generational 26834553 Long P , et al. (2016)
c.882_883insATT p.Thr294_Gln295insIle inframe_insertion Familial Maternal Simplex 32530565 Suzuki T et al. (2020)
Common Variants  

No common variants reported.

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."

7/1/2020
1
icon
1

Score remained at 1

Description

The protein encoded by the ARHGEF9 gene, collybistin (CB), was shown to physically interact with mTOR and inhibit mTORC1 signaling pathway and protein synthesis (Machado et al., 2016). A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy in Machado et al., 2016; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions. A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

The protein encoded by the ARHGEF9 gene, collybistin (CB), was shown to physically interact with mTOR and inhibit mTORC1 signaling pathway and protein synthesis (Machado et al., 2016). A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy in Machado et al., 2016; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions. A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

The protein encoded by the ARHGEF9 gene, collybistin (CB), was shown to physically interact with mTOR and inhibit mTORC1 signaling pathway and protein synthesis (Machado et al., 2016). A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy in Machado et al., 2016; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions. A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Reports Added
[Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019]
4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

The protein encoded by the ARHGEF9 gene, collybistin (CB), was shown to physically interact with mTOR and inhibit mTORC1 signaling pathway and protein synthesis (Machado et al., 2016). A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy in Machado et al., 2016; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions. A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
7/1/2018
4S
icon
4S

Decreased from 4S to 4S

Description

The protein encoded by the ARHGEF9 gene, collybistin (CB), was shown to physically interact with mTOR and inhibit mTORC1 signaling pathway and protein synthesis (Machado et al., 2016). A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy in Machado et al., 2016; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions. A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Reports Added
[Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation.2018]
10/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

The protein encoded by the ARHGEF9 gene, collybistin (CB), was shown to physically interact with mTOR and inhibit mTORC1 signaling pathway and protein synthesis (Machado et al., 2016). A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy in Machado et al., 2016; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions. A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Reports Added
[ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.2017]
7/1/2017
icon
4S

Increased from to 4S

Description

The protein encoded by the ARHGEF9 gene, collybistin (CB), was shown to physically interact with mTOR and inhibit mTORC1 signaling pathway and protein synthesis (Machado et al., 2016). A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy in Machado et al., 2016; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions. A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Reports Added
[ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.2017] [Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
Krishnan Probability Score

Score 0.57648525012354

Ranking 639/25841 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 0.98306539432328

Ranking 2043/18225 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 0.93460409117401

Ranking 12619/18665 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
Zhang D Score

Score 0.2415051994869

Ranking 3602/20870 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
GPHN gephyrin Human Protein Binding 10243 Q9NQX3
MTOR mechanistic target of rapamycin (serine/threonine kinase) Human Protein Binding 2475 P42345
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