Human Gene Module / Chromosome 1 / ARID1A

ARID1AAT-rich interaction domain 1A

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
4 / 9
Rare Variants / Common Variants
8 / 0
Aliases
-
Associated Syndromes
Coffin-Siris syndrome 2
Chromosome Band
1p36.11
Associated Disorders
-
Relevance to Autism

Trio-exome sequencing of 745 participants with NDD and/or epilepsy from the Center for Medical Genetics of the University Hospital Antwerp in Smal et al., 2024 identified a de novo mosaic nonsense variant in the ARID1A gene (NM_139135.4:c.1687C>T;p.Gln563Ter) in a patient presenting with autism spectrum disorder, severe intellectual disability, and epilepsy. Two additional de novo nonsense variants and four de novo missense variants in the ARID1A gene have been identified in ASD probands from the SPARK cohort (Zhou et al., 2022; Fu et al., 2022). Heterozygous variants in ARID1A was also responsible for Coffin-Siris syndrome 2 (OMIM 614607); autism spectrum disorder was reported in 2/15 (13%) individuals with ARID1A-associated Coffin-Siris syndrome from the CSS/BAF complex registry in Vasko et al., 2021. Knockout of ARID1A in human embryonic stem cells (hESCs) in Liu et al., 2020 was found to result in spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESC; furthermore, when compared with wild-type hESCs, cardiac differentiation from ARID1A -/- hESCs was prominently suppressed, whereas neural differentiation was significantly promoted. Arid1a conditional knockout mice were found to exhibit reduced cortical thickness in the developing cortex, inhibition in the proliferation of radial glial cells, increased cell death during late cortical development, and dysregulated expression of genes associated with proliferation and differentiation (Liu et al., 2021).

Molecular Function

Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Binds DNA non-specifically. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, a

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Reports related to ARID1A (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support - Juli Liu et al. (2020) No -
3 Support - Ashley Vasko et al. (2021) No ASD
4 Support - Xiao Liu et al. (2021) No -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Fu JM et al. (2022) Yes -
7 Primary - Noor Smal et al. () Yes ID, epilepsy/seizures
8 Support - Samantha M Barnada et al. (2024) No -
9 Support - Pleuntje J van der Sluijs et al. () No Autistic traits, stereotypy
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3036T>G p.Tyr1012Ter stop_gained De novo - - 35982160 Fu JM et al. (2022)
c.312C>G p.Asn104Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.914C>T p.Ala305Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1687C>T p.Gln563Ter stop_gained De novo - Simplex 38965372 Noor Smal et al. ()
c.3541A>G p.Arg1181Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6794C>T p.Pro2265Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5055A>G p.Thr1685= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2415A>T p.Pro805= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

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.

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."

10/1/2024
3S

Initial score established: 3S

Krishnan Probability Score

Score 0.61038769277971

Ranking 230/25841 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 0.99999999664269

Ranking 120/18225 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 0.94825284733461

Ranking 17608/18665 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 0.35969066701984

Ranking 1903/20870 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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