ARID1A – Coffin-Siris syndrome

Coffin-Siris syndrome (CSS) is a rare autosomal dominant neurodevelopmental disorder characterized by intellectual disability, coarse facial features, hypoplasia of the fifth digits’ nails, and variable organ system anomalies (MONDO:0015452). Pathogenic variants in ARID1A, encoding a subunit of the mSWI/SNF (BAF) chromatin remodeling complex, cause CSS type 2 (ARID1A-CSS).

Multiple case series and case reports have identified de novo truncating ARID1A variants in individuals with CSS. In a prenatal cohort of 44 patients with CSS-associated genes, pathogenic ARID1A variants were observed in 16 fetuses (36%), including c.175G>T (p.Glu59Ter) ([PMID:34942405]). A separate cohort focusing on prenatal CSS phenotypes confirmed frequent ARID1A involvement in anomalies such as agenesis of the corpus callosum and diaphragmatic hernia ([PMID:35579625]).

Genetic analyses in large postnatal cohorts further support the association. In a registry of 376 CSS patients, pathogenic ARID1A variants accounted for 6 of 78 identified BAF complex gene alterations ([PMID:31530938]). Together, over 22 unrelated probands with de novo ARID1A loss-of-function variants have been reported, with consistent AD inheritance and no evidence of recessive alleles.

The variant spectrum in ARID1A-CSS is dominated by loss-of-function alleles: nonsense, frameshift, splice-site and whole-gene deletions. The recurrent prenatal variant c.175G>T (p.Glu59Ter) exemplifies this pattern. No recurrent founder alleles have been described, and mosaicism has been reported in a minority of cases.

Mechanistically, ARID1A variants act via haploinsufficiency. Studies in cancer and cellular models show that ARID1A loss impairs nuclear import, destabilizes protein via proteasomal degradation, and disrupts PI3K/AKT and PTEN signaling ([PMID:34942405]). These findings are concordant with the multisystem developmental anomalies seen in ARID1A-CSS.

Functional evidence from non-CSS studies demonstrates that ARID1A deficiency compromises chromatin remodeling and transcriptional regulation. In endometrial cancer models, ARID1A knockdown leads to G2/M arrest and increased apoptosis, highlighting its role in cell proliferation control ([PMID:30358215]). While these data derive from somatic contexts, they underscore haploinsufficiency as the pathogenic mechanism in germline CSS.

No studies refute the ARID1A-CSS association. The phenotypic concordance across prenatal and postnatal cohorts, the consistent LoF variant pattern, and mechanistic data support a Strong clinical validity classification. ARID1A testing should be incorporated into genetic panels for individuals with CSS features or non-isolated congenital diaphragmatic hernia. Key take-home: ARID1A haploinsufficiency is a well-established cause of autosomal dominant Coffin-Siris syndrome with clear diagnostic and management implications.

References

• European journal of medical genetics • 2022 • Prenatal presentation of multiple anomalies associated with haploinsufficiency for ARID1A. PMID:34942405
• Genetics in medicine : official journal of the American College of Medical Genetics • 2022 • Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort. PMID:35579625
• Journal of human genetics • 2019 • Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients. PMID:31530938

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