ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22426308 Using exome sequencing Tsurusaki et al (2012) identified 3 variants in ARID1A in a study designed to target genes encoding sub-units of the SWItch/Sucrose NonFermenting (SWI/SNF) complex in patients with Coffin-Siris Syndrome (CSS). These included one frameshift and 2 premature termination variants. 1 of the nonsense variants was de novo (subject 8); parental samples for the remaining 2 variants were unavailable. cDNA analysis of lymphoblastoid cell lines from subject 6 (the nonsense variant without available parental samples) showed that the mutant transcript was subject to nonsense-mediated decay. The authors proposed that haploinsufficiency of ARID1A must be able to cause CSS as the mutations were predicted to cause protein truncation. Additional clinical information for these three individuals is available in PMID: 23637025.
23929686 Santen et al. 2013 evaluated 63 patients with clinical diagnoses of Coffin-Siris syndrome via Sanger sequencing for variants in six genes previously associated with Coffin-Siris syndrome, including ARID1A. They identified 4 variants in ARID1A: two nonsense and two frameshift. One of the nonsense and one of the frameshift variants were de novo; the mother was unavailable for the second nonsense variant (not detected in father), and neither parent was available for the second frameshift. Of note, all 4 of these variants appeared to be mosaic in lymphocytes. These authors also suggested that the sequencing reads from the variant alleles published in the Tsurusaki paper of two variants appeared to have lower peaks than the reference allele; they hypothesized that these variants might be mosaic as well.
23906836 Wieczorek et al. 2013 describe a de novo nonsense variant in an individual with a clinical diagnosis of Coffin-Siris syndrome (Individual K2435) identified by whole exome sequencing. The authors note that this allele was "detected in a lower proportion than the wild-type allele, indicating the presence of somatic mosaicism in the individual."

Haploinsufficiency phenotype comments:

Coffin-Siris syndrome is a rare congenital anomaly syndrome characterized by growth deficiency, intellectual disability, microcephaly, coarse facial features and hypoplastic nail of the fifth finger and/or toe. Variants reported in the literature to date have been nonsense or frameshift, though many have been observed in the context of somatic mosaicism. One hypothesis put forth by Santen et al. is that heterozygous truncating germline variants in ARID1A may be embryonically lethal; these authors cite the work of Gao et al. (2008) showing this to be the case in mice.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Bidart et al. 2017 (PMID: 27906199) describe 4 individuals with de novo duplications involving ARID1A (and other genes). The authors classified the phenotypes of the individuals as "similar" with "microcephaly, intellectual disability, delayed motor milestones, hand and foot anomalies, growth impairment, constipation, frequent airway infections, dysmorphic facial features, and stereotypies." The minimal critical region between these 4 individuals included all of ARID1A as well as part of the PIGV gene. PIGV expression did not appear to be deregulated according to RNA-seq and qRT-PCR assays, but there was a 1.5-fold increase in ARID1A expression compared to controls by qRT-PCR. Subsequent western blot confirmed a slight, but significant increase in ARID1A protein expression. Coutton et al. 2013 (PMID: 23521658) describe an individual with a 190-kb de novo duplication involving ARID1A (and PIGV, ZDHHC18, and SFN). The authors describe the phenotype of the proband overlapping those with Coffin-Siris syndrome (CSS) and hyperphosphatasia mental retardation syndrome (HPMP, also known as Mabry syndrome). RT-MLPA of mRNA demonstrated a 1.5-fold and 3-fold increased expression of ARID1A and PIGV, respectively. Homozygous and compound heterozygous pathogenic variants in PIGV is associated with autosomal recessive HRMP (OMIM 610274, MIM 239300). Because these duplications all include other genes, we will not formally count this as evidence for triplosensitivity. Additional evidence is needed to evaluate the potential consequences of full gene duplications of ARID1A.