Human Gene Module / Chromosome 12 / ARID2

ARID2AT-rich interaction domain 2

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
8 / 20
Rare Variants / Common Variants
57 / 0
Aliases
ARID2, BAF200,  CSS6,  p200
Associated Syndromes
Coffin-Siris syndrome 6, Coffin-Siris syndrome 6, DD, ID, Coffin-Siris syndrome 6, DD
Chromosome Band
12q12
Associated Disorders
DD/NDD, ADHD, ID
Relevance to Autism

A de novo missense variant that was predicted to be damaging was observed in the ARID2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo splice-site variant in this gene was identified in an ASD proband from the ASPIRE cohort in Callaghan et al., 2019. Heterozygous variants in the ARID2 gene are also associated with a form of Coffin-Siris syndrome (Coffin-Siris syndrome 6; OMIM 617808); in addition to intellectual disability and dysmorphic features, individuals with this syndrome frequently present with behavioral abnormalities such as ADHD, tics, and autistic behavior such as routine-driven and/or rigid behavior and hand-flapping (Shang et al., 2015; Branswig et al., 2017; Van Paemel et al., 2017; Gazdagh et al., 2019).

Molecular Function

This gene encodes a member of the AT-rich interactive domain (ARID)-containing family of DNA-binding proteins. Members of the ARID family have roles in embryonic patterning, cell lineage gene regulation, cell cycle control, transcriptional regulation and chromatin structure modification. This protein functions as a subunit of the polybromo- and BRG1-associated factor or PBAF (SWI/SNF-B) chromatin remodeling complex which facilitates ligand-dependent transcriptional activation by nuclear receptors.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ARID2 (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Mutations in ARID2 are associated with intellectual disabilities Shang L , et al. (2015) No DD, ID, ADHD
3 Support Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype Bramswig NC , et al. (2017) No -
4 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
5 Support Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability Van Paemel R , et al. (2017) No -
6 Support Extending the clinical and genetic spectrum of ARID2 related intellectual disability. A case series of 7 patients Gazdagh G , et al. (2018) No -
7 Recent Recommendation Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
8 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) No -
9 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
10 Support - Lee Y et al. (2021) No -
11 Support - Hu C et al. (2022) Yes -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Wang J et al. (2023) Yes -
14 Support - Balasar et al. (2023) No -
15 Support - Sanchis-Juan A et al. (2023) No Epilepsy/seizures
16 Support - M Cecilia Poli et al. () Yes -
17 Support - Samantha A Schrier Vergano et al. (2024) No ASD, ADHD, ID, epilepsy/seizures
18 Support - Alistair T Pagnamenta et al. (2024) No -
19 Support - Ayyappan Anitha et al. (2024) Yes -
20 Support - Axel Schmidt et al. (2024) No ASD, epilepsy/seizures
Rare Variants   (57)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 34706719 Lee Y et al. (2021)
- - copy_number_loss - - - 28884947 Van Paemel R , et al. (2017)
- - copy_number_loss Unknown - - 29698805 Gazdagh G , et al. (2018)
c.4444C>T p.Gln1482Ter stop_gained De novo - - 28135719 et al. (2017)
c.2983C>T p.Gln995Ter stop_gained De novo - - 35741772 Hu C et al. (2022)
c.2377C>T p.Gln793Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
- - inversion De novo - Simplex 38776926 Alistair T Pagnamenta et al. (2024)
c.1028T>A p.Leu343Ter stop_gained Unknown - - 26238514 Shang L , et al. (2015)
- - inversion Familial Maternal - 38776926 Alistair T Pagnamenta et al. (2024)
c.4318C>T p.Gln1440Ter stop_gained De novo - - 26238514 Shang L , et al. (2015)
c.399C>G p.Tyr133Ter stop_gained De novo - - 29698805 Gazdagh G , et al. (2018)
c.940C>T p.Arg314Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1652C>T p.Ser551Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2T>G p.Met1? initiator_codon_variant Unknown - - 33004838 Wang T et al. (2020)
c.4444C>T p.Gln1482Ter stop_gained De novo - - 29698805 Gazdagh G , et al. (2018)
- - copy_number_loss Unknown - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.5036G>A p.Arg1679Gln missense_variant De novo - - 33004838 Wang T et al. (2020)
c.5141C>T p.Ser1714Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1330+1G>A - splice_site_variant De novo - - 31038196 Callaghan DB , et al. (2019)
c.327T>G p.Asp109Glu initiator_codon_variant Unknown - - 33004838 Wang T et al. (2020)
c.625G>A p.Val209Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1158dup p.Asn387Ter frameshift_variant De novo - - 29698805 Gazdagh G , et al. (2018)
c.4687_4690dup p.Thr1564LysfsTer5 frameshift_variant De novo - - 28135719 et al. (2017)
c.2796A>G p.Pro932%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2122C>T p.Pro708Ser missense_variant Unknown - Unknown 32530565 Suzuki T et al. (2020)
c.4390C>T p.Arg1464Cys missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.940C>T p.Arg314Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2645_2646insCT p.Val883LeufsTer10 frameshift_variant De novo - - 28135719 et al. (2017)
c.2406del p.Phe802LeufsTer20 frameshift_variant De novo - - 26238514 Shang L , et al. (2015)
c.26del p.Pro9LeufsTer49 frameshift_variant De novo - - 28124119 Bramswig NC , et al. (2017)
c.4310del p.Ala1437GlyfsTer16 frameshift_variant De novo - - 26238514 Shang L , et al. (2015)
c.300del p.Tyr100Ter frameshift_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.1932_1936del p.Gln644HisfsTer61 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.2114del p.Ser705IlefsTer53 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.2872C>T p.Gln958Ter stop_gained De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.4867G>C p.Asp1623His missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.5198T>C p.Ile1733Thr missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3680C>T p.Gln1227Ter stop_gained De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.5070C>G p.His1690Gln stop_gained Unknown - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.5260C>T p.Arg1754Ter stop_gained De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.5305C>T p.Arg1769Ter stop_gained De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.1746_1747del p.Arg582SerfsTer6 frameshift_variant De novo - - 38177409 M Cecilia Poli et al. ()
c.4425del p.Ser1476LeufsTer9 frameshift_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.4687_4690dup p.Thr1564LysfsTer5 frameshift_variant De novo - - 29698805 Gazdagh G , et al. (2018)
c.2645_2646insCT p.Val883LeufsTer10 frameshift_variant De novo - - 29698805 Gazdagh G , et al. (2018)
c.1784_1785del p.His595ArgfsTer30 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.5399_5402dup p.Ile1802SerfsTer3 frameshift_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.3280_3281del p.Ser1094ProfsTer10 frameshift_variant De novo - - 28124119 Bramswig NC , et al. (2017)
c.857_902del p.Val286AlafsTer27 frameshift_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.237del p.Arg80GlufsTer10 frameshift_variant De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.415del p.Ser139ArgfsTer76 frameshift_variant De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.1332del p.Asp444GlufsTer3 frameshift_variant Unknown - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.1199del p.Tyr400SerfsTer16 frameshift_variant De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.2814_2815del p.Tyr939CysfsTer11 frameshift_variant Unknown - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.4255_4256del p.Pro1419CysfsTer24 frameshift_variant De novo - - 38243407 Samantha A Schrier Vergano et al. (2024)
c.1486G>C p.Ala496Pro missense_variant Unknown - Multiplex (monozygotic twins) 39038432 Ayyappan Anitha et al. (2024)
c.4634A>G p.Asn1545Ser missense_variant Unknown - Multiplex (monozygotic twins) 39038432 Ayyappan Anitha et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo missense variant that was predicted to be damaging was observed in the ARID2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo splice-site variant in this gene was identified in an ASD proband from the ASPIRE cohort in Callaghan et al., 2019. Heterozygous variants in the ARID2 gene are also associated with a form of Coffin-Siris syndrome (Coffin-Siris syndrome 6; OMIM 617808); in addition to intellectual disability and dysmorphic features, individuals with this syndrome frequently present with behavioral abnormalities such as ADHD, tics, and autistic behavior such as routine-driven and/or rigid behavior and hand-flapping (Shang et al., 2015; Branswig et al., 2017; Van Paemel et al., 2017; Gazdagh et al., 2019).

Score Delta: Score remained at 2S

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.

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."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo missense variant that was predicted to be damaging was observed in the ARID2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo splice-site variant in this gene was identified in an ASD proband from the ASPIRE cohort in Callaghan et al., 2019. Heterozygous variants in the ARID2 gene are also associated with a form of Coffin-Siris syndrome (Coffin-Siris syndrome 6; OMIM 617808); in addition to intellectual disability and dysmorphic features, individuals with this syndrome frequently present with behavioral abnormalities such as ADHD, tics, and autistic behavior such as routine-driven and/or rigid behavior and hand-flapping (Shang et al., 2015; Branswig et al., 2017; Van Paemel et al., 2017; Gazdagh et al., 2019).

10/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo missense variant that was predicted to be damaging was observed in the ARID2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo splice-site variant in this gene was identified in an ASD proband from the ASPIRE cohort in Callaghan et al., 2019. Heterozygous variants in the ARID2 gene are also associated with a form of Coffin-Siris syndrome (Coffin-Siris syndrome 6; OMIM 617808); in addition to intellectual disability and dysmorphic features, individuals with this syndrome frequently present with behavioral abnormalities such as ADHD, tics, and autistic behavior such as routine-driven and/or rigid behavior and hand-flapping (Shang et al., 2015; Branswig et al., 2017; Van Paemel et al., 2017; Gazdagh et al., 2019).

Reports Added
[Prevalence and architecture of de novo mutations in developmental disorders2017] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo missense variant that was predicted to be damaging was observed in the ARID2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo splice-site variant in this gene was identified in an ASD proband from the ASPIRE cohort in Callaghan et al., 2019. Heterozygous variants in the ARID2 gene are also associated with a form of Coffin-Siris syndrome (Coffin-Siris syndrome 6; OMIM 617808); in addition to intellectual disability and dysmorphic features, individuals with this syndrome frequently present with behavioral abnormalities such as ADHD, tics, and autistic behavior such as routine-driven and/or rigid behavior and hand-flapping (Shang et al., 2015; Branswig et al., 2017; Van Paemel et al., 2017; Gazdagh et al., 2019).

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo missense variant that was predicted to be damaging was observed in the ARID2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo splice-site variant in this gene was identified in an ASD proband from the ASPIRE cohort in Callaghan et al., 2019. Heterozygous variants in the ARID2 gene are also associated with a form of Coffin-Siris syndrome (Coffin-Siris syndrome 6; OMIM 617808); in addition to intellectual disability and dysmorphic features, individuals with this syndrome frequently present with behavioral abnormalities such as ADHD, tics, and autistic behavior such as routine-driven and/or rigid behavior and hand-flapping (Shang et al., 2015; Branswig et al., 2017; Van Paemel et al., 2017; Gazdagh et al., 2019).

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

Increased from to 4S

Description

A de novo missense variant that was predicted to be damaging was observed in the ARID2 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, while a de novo splice-site variant in this gene was identified in an ASD proband from the ASPIRE cohort in Callaghan et al., 2019. Heterozygous variants in the ARID2 gene are also associated with a form of Coffin-Siris syndrome (Coffin-Siris syndrome 6; OMIM 617808); in addition to intellectual disability and dysmorphic features, individuals with this syndrome frequently present with behavioral abnormalities such as ADHD, tics, and autistic behavior such as routine-driven and/or rigid behavior and hand-flapping (Shang et al., 2015; Branswig et al., 2017; Van Paemel et al., 2017; Gazdagh et al., 2019).

Krishnan Probability Score

Score 0.57157283085621

Ranking 770/25841 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 0.9999990531281

Ranking 297/18225 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
Iossifov Probability Score

Score 0.866

Ranking 179/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.87027442745232

Ranking 4316/18665 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 0.52724919724932

Ranking 342/20870 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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