Relevance to Autism

Two de novo frameshift variants in the ARID1B gene were identified by exome sequencing in unrelated simplex ASD cases (PMIDs 22495309 and 23160955). Nord et al., 2011 (PMID 21448237) had previously identified a de novo deletion within the ARID1B gene resulting in reduced transcript expression in a patient with autism, and a de novo translocation and deletions disrupting ARID1B had previously been identified in ASD patients in Halgren et al., 2011 (PMID 21801163). Three additional de novo loss-of-function variants in ARID1B were identified in ASD probands from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014. Furthermore, analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from ASC in this report identified ARID1B as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified ARID1B as a gene reaching exome-wide significance (P < 2.5E-06). Variants in ARID1B are also responsible for Coffin-Siris syndrome (CSS); a subset of CSS patients have been reported to show ASD or autistic features (PMIDs 22426309, 24569609).

Molecular Function

This locus encodes an AT-rich DNA interacting domain-containing protein. The encoded protein is a component of the SWI/SNF chromatin remodeling complex and may play a role in cell-cycle activation. The protein encoded by this locus is similar to AT-rich interactive domain-containing protein 1A. These two proteins function as alternative, mutually exclusive ARID-subunits of the SWI/SNF complex. The associated complexes play opposing roles.

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Model Summary

Arid1b heterozygous mice showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders, including deficiency in insulin-like growth factor 1. Supplementation with growth hormone restored muscle weakness and growth retardation in Arid1b heterozygous mice.

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