Submission Details

ARID1B was reported in relation to autosomal dominant Coffin-Siris syndrome by three different groups around the same time in 2012 (Tsurusaki, et al., PMID: 22426308; Santen, et al., PMID: 22426309; Hoyer, et al., PMID: 22405089). Coffin-Siris syndrome is characterized by intellectual disability associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. More than 170 unique pathogenic or likely pathogenic variants in ARID1B have been reported in ClinVar, with the majority of them de novo truncating variants (van der Sluijs, et al., PMID: 30349098). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Hoyer, et al., PMID: 22405089). The gene-disease association is also supported by animal and cell culture models. Noteworthy, Coffin-Siris syndrome can be caused by variants in additional genes, including ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, SMARCC2, SOX11, and SOX4 (see OMIM). In summary, ARID1B is definitively associated with 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 12/02/19 (SOP Version 7).