Human Gene Module / Chromosome 11 / ARHGAP32

ARHGAP32Rho GTPase activating protein 32

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 10
Rare Variants / Common Variants
12 / 0
Aliases
ARHGAP32, GC-GAP,  GRIT,  PX-RICS,  RICS,  p200RhoGAP,  p250GAP
Associated Syndromes
Jacobsen syndrome
Chromosome Band
11q24.3
Associated Disorders
ASD
Relevance to Autism

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016).

Molecular Function

RICS, the protein encoded by the ARHGAP32 gene, is a neuron-associated GTPase-activating protein that may regulate dendritic spine morphology and strength by modulating Rho GTPase.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ARHGAP32 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q Akshoomoff N , et al. (2014) No ASD/autistic features
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking Nakamura T , et al. (2016) No -
4 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
5 Support The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice Nakamura T , et al. (2018) No -
6 Support De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis Wang S , et al. (2018) No -
7 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 25058499 Akshoomoff N , et al. (2014)
- - copy_number_loss Unknown - - 25058499 Akshoomoff N , et al. (2014)
c.1219C>T p.Arg407Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4682T>G p.Leu1561Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.714G>A p.Trp238Ter stop_gained De novo - Simplex 30257206 Wang S , et al. (2018)
c.4869T>C p.Tyr1623%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 25058499 Akshoomoff N , et al. (2014)
c.5284C>T p.Arg1762Trp missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.5210A>G p.Asp1737Gly missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.4713del p.Glu1572LysfsTer22 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.5625C>G p.Ser1875Arg missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.5804dup p.Leu1935PhefsTer20 frameshift_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016). A de novo frameshift variant in ARHGAP32 was identified in a female Chinese proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort who presented with ASD and intellectual disability in Wang 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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016). A de novo frameshift variant in ARHGAP32 was identified in a female Chinese proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort who presented with ASD and intellectual disability in Wang et al., 2016.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016). A de novo frameshift variant in ARHGAP32 was identified in a female Chinese proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort who presented with ASD and intellectual disability in Wang et al., 2016.

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

Decreased from 4 to 4

Description

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016). A de novo frameshift variant in ARHGAP32 was identified in a female Chinese proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort who presented with ASD and intellectual disability in Wang et al., 2016.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016). A de novo frameshift variant in ARHGAP32 was identified in a female Chinese proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort who presented with ASD and intellectual disability in Wang et al., 2016.

Reports Added
[De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.2018]
7/1/2018
4
icon
4

Decreased from 4 to 4

Description

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016). A de novo frameshift variant in ARHGAP32 was identified in a female Chinese proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort who presented with ASD and intellectual disability in Wang et al., 2016.

Reports Added
[The Autism-Related Protein PX-RICS Mediates GABAergic Synaptic Plasticity in Hippocampal Neurons and Emotional Learning in Mice.2018]
10/1/2016
5
icon
4

Decreased from 5 to 4

Description

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016). A de novo frameshift variant in ARHGAP32 was identified in a female Chinese proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort who presented with ASD and intellectual disability in Wang et al., 2016.

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
4/1/2016
icon
5

Increased from to 5

Description

Jacobsen syndrome is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11 characterized by intellectual disability and dysmorphic features. 8 of 17 Jacobsen syndrome patients (47%) described in Akshoomoff et al., 2015 exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis, leading to the identification of an autism "critical region" in distal 11q deletions containing four genes, including ARHGAP32, in this report. Mice that are deficient for PX-RICS, a longer splicing isoform of ARHGAP32, exhibit ASD-like social behaviors and ASD-related comorbidities, show reduced surface levels of gamma-aminobutyric acid type A receptor (GABAAR), and display impaired GABAAR-mediated synaptic transmission (Nakamura et al., 2016).

Krishnan Probability Score

Score 0.52899384990121

Ranking 1571/25841 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 0.98708851950848

Ranking 1920/18225 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 0.90842581827239

Ranking 7324/18665 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 0.5137751609408

Ranking 414/20870 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
ASB3 ankyrin repeat and SOCS box containing 3 Human Protein Binding 51130 Q9Y575
Dctn1 dynactin 1 Mouse Protein Binding 13191 O08788
Gabarap gamma-aminobutyric acid receptor associated protein Mouse Protein Binding 56486 Q9DCD6
Gabra1 Gamma-aminobutyric acid receptor subunit alpha-1 Mouse Protein Binding 14394 P62812
Gabrg2 Gamma-aminobutyric acid receptor subunit gamma-2 Mouse Protein Binding 14406 P22723
GRIN2B glutamate receptor, ionotropic, N-methyl D-aspartate 2B Human Protein Binding 2904 Q13224
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