Submission Details

Autosomal dominant

06/21/2019

The ARID1A gene is located on chromosome 1 at 1p36.11 and encodes the AT-rich interaction domain 1A. This protein is a component of the SWI/SNF complex and plays an important role in chromatin remodeling and DNA transcription, replication, and repair. It also functions in regulating neural stem cell fate and brain development. The ARID1A gene was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2012 (22426308: Tsurusaki et al. 2012). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least eight unique variants in this gene have been reported in at least three publications (22426308: Tsurusaki et al. 2012; 23929686: Santen et al. 2013; 23906836: Wieczorek et al. 2013). None of the variants were inherited, and at least three were proven de novo. The maximum score for genetic evidence has been reached. Loss of function is implicated as the mechanism of disease; all eight variants curated were heterozygous predicted null, although a truncated protein rather than nonsense-mediated decay was expected for three of the variants. This gene-disease relationship is supported by biochemical pathway (30123105: Bögershausen et al. 2018), protein interaction (20522713: Krosl et al. 2010), and animal model data (26806701: Chandler et al. 2016), as homozygous neural crest cell-specific null mice exhibit embryonic lethality but also features that overlap with the human disease. Heterozyous conditional null mice also partially recapitulate the phenotype. In summary, there is strong evidence to support the relationship between ARID1A and Coffin-Siris syndrome (autosomal dominant). Additional reports in human published after the first proposal of the association are needed to reach a definitive classification.

23929686 22426308 23906836 30123105 20522713 26806701 26716708