Human Gene Module / Chromosome 1 / ARHGEF2

ARHGEF2Rho/Rac guanine nucleotide exchange factor 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1q22
Associated Disorders
-
Relevance to Autism

A number of de novo variants in the ARHGEF2 gene, including three potenitally deleterious de novo missense variants, have been identiified in ASD probands (De Rubeis et al., 2014; Yuen et al., 2017; Turner et al., 2017; Guo et al., 2019; Satterstrom et al., 2020). A de novo non-coding variant that was predicted to target the ARHGEF2 gene via chromatin interactions was identified in a Korean ASD proband from a simplex family in Kim et al., 2022; functional analysis in human induced pluripotent stem cells derived from the proband and the proband's parents demonstrated that this variant resulted in significantly reduced levels of ARHGEF2 expression in patient-derived hiPSCs compared to parent-derived hiPSCs.

Molecular Function

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate rho-dependent signals. Homozygous mutations in this gene are responsible for neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM; OMIM 617523), a disorder characterized by intellectual disability and speech delay associated with mild microcephaly and midbrain-hindbrain malformations on brain imaging (Ravindran et al., 2017).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ARHGEF2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support - Ravindran E et al. (2017) No -
4 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
5 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
6 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
7 Recent Recommendation - Kim IB et al. (2022) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2260-77G>T - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.470+24G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
g.155445465T>C - intergenic_variant De novo - Simplex 35840799 Kim IB et al. (2022)
c.1043C>T p.Ala348Val missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.63+3844_63+3855del - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1565C>T p.Ser522Leu missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1030C>T p.Arg344Cys missense_variant De novo - Multiplex 30504930 Guo H , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2022
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3

Increased from to 3

Krishnan Probability Score

Score 0.49592679565932

Ranking 2743/25841 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 0.99999323549835

Ranking 419/18225 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 0.9432156038709

Ranking 15602/18665 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 0.57288010490352

Ranking 164/20870 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
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