Human Gene Module / Chromosome 12 / ARID2

ARID2AT-rich interaction domain 2

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 9
Rare Variants / Common Variants
29 / 0
Aliases
ARID2, BAF200,  CSS6,  p200
Associated Syndromes
Coffin-Siris syndrome 6
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
12q12
Associated Disorders
DD/NDD, ID, ADHD
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.

Reports related to ARID2 (9 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 -
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - 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 NA - 28135719 et al. (2017)
c.2377C>T p.Gln793Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.1028T>A p.Leu343Ter stop_gained Unknown - - 26238514 Shang L , et al. (2015)
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.4318C>T p.Gln1440Ter stop_gained De novo NA - 26238514 Shang L , et al. (2015)
c.399C>G p.Tyr133Ter stop_gained De novo NA - 29698805 Gazdagh G , et al. (2018)
c.5141C>T p.Ser1714Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4444C>T p.Gln1482Ter stop_gained De novo NA - 29698805 Gazdagh G , et al. (2018)
c.5036G>A p.Arg1679Gln missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1330+1G>A - splice_site_variant De novo NA - 31038196 Callaghan DB , et al. (2019)
c.327T>G p.Asp109Glu initiator_codon_variant Unknown - - 33004838 Wang T et al. (2020)
c.1158dup p.Asn387Ter frameshift_variant De novo NA - 29698805 Gazdagh G , et al. (2018)
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.4687_4690dup p.Thr1564LysfsTer5 frameshift_variant De novo NA - 28135719 et al. (2017)
c.940C>T p.Arg314Cys missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.2645_2646insCT p.Val883LeufsTer10 frameshift_variant De novo NA - 28135719 et al. (2017)
c.300del p.Tyr100Ter frameshift_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.2406del p.Phe802LeufsTer20 frameshift_variant De novo NA - 26238514 Shang L , et al. (2015)
c.26del p.Pro9LeufsTer49 frameshift_variant De novo NA - 28124119 Bramswig NC , et al. (2017)
c.4310del p.Ala1437GlyfsTer16 frameshift_variant De novo NA - 26238514 Shang L , et al. (2015)
c.1932_1936del p.Gln644HisfsTer61 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.4687_4690dup p.Thr1564LysfsTer5 frameshift_variant De novo NA - 29698805 Gazdagh G , et al. (2018)
c.2645_2646insCT p.Val883LeufsTer10 frameshift_variant De novo NA - 29698805 Gazdagh G , et al. (2018)
c.3280_3281del p.Ser1094ProfsTer10 frameshift_variant De novo NA - 28124119 Bramswig NC , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, 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 4S

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.

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."

10/1/2020
4S
icon
4S

Score remained at 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).

7/1/2020
4S
icon
4S

Score remained at 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).

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.
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
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
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).
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.
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