Submission Details

ARID2 - Coffin-Siris syndrome

ARID2 was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2015 by Shang et al. (PMID: 26238514), who reported four individuals with truncating variants. Common phenotypes include mild to moderate intellectual disability, variable behavioral abnormalities, and dysmorphic facial features with coarsening that becomes more apparent with age. The majority of variants are de novo, although in at least one individual the variant was inherited from a mildly affected mother (PMID: 35813374). Heterozygous truncating variants in seven patients, reported in three publications, are included in this curation (PMIDs: 26238514, 28124119, 35813374). More evidence is available in the literature (PMIDs: 28884947, 29698805,34205270), but the maximum genetic evidence score (12 points) has been reached.

The mechanism of pathogenicity is loss of function, supported by a pLI score of 1 (gnomAD v2.1.1). This gene-disease relationship is also supported by biochemical function, protein interaction, a mouse model and in vitro functional assays. ARID2 is an intrinsic component of polybromo brahma-associated factor (PBAF), a SWI/SNF subcomplex involved in chromatin remodeling. Arid2 haploinsufficient mice exhibit learning and memory deficits in the Morris water maze and reduced body size (PMID: 33051312). ARID2 haploinsufficiency also enhanced RAS-MAPK pathway activity in vitro (PMID: 33051312).

In summary, there is definitive evidence to support the relationship between ARID2 and autosomal dominant Coffin-Siris syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 7, 2022 (SOP Version 9).

ARID2 was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2015 by Shang et al. (PMID: 26238514), who reported four individuals with truncating variants. Common phenotypes include mild to moderate intellectual disability, variable behavioral abnormalities, and dysmorphic facial features with coarsening that becomes more apparent with age.

Seven heterozygous truncating variants that have been reported in seven probands in three publications (PMIDs: 26238514, 28124119, 35813374) are included in this curation. More evidence is available in the literature (PMIDs: 28884947, 29698805, 34205270), but the maximum score for genetic evidence (12 points) has been reached. The majority of variants are de novo, although in at least one individual the variant was inherited from a mildly affected mother (PMID: 35813374). The mechanism of pathogenicity is loss of function, supported by a pLI score of 1 (gnomAD v2.1.1).

This gene-disease relationship is also supported by biochemical function, protein interaction, a mouse model and in vitro functional assays. ARID2 is an intrinsic component of polybromo brahma-associated factor (PBAF), a SWI/SNF subcomplex involved in chromatin remodeling. Arid2 haploinsufficient mice exhibit learning and memory deficits in the Morris water maze and reduced body size (PMID: 33051312). ARID2 haploinsufficiency also enhanced RAS-MAPK pathway activity in vitro (PMID: 33051312).

In summary, there is definitive evidence supporting the relationship between ARID2 and autosomal dominant Coffin-Siris syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 7, 2022 (SOP Version 9).