ARID1B – Coffin-Siris syndrome 1

Coffin-Siris syndrome 1 (CSS1) is a multiple malformation disorder characterized by intellectual disability, coarse facial features, hypertrichosis, sparse scalp hair, and hypoplasia or absence of fifth fingernails or toenails. ARID1B encodes BAF250B, a subunit of the SWI/SNF chromatin-remodeling complex, and is the most commonly mutated gene in CSS1.

Heterozygous ARID1B variants have been reported in over 100 unrelated CSS1 probands. In a study of 49 patients, truncating ARID1B mutations were detected in 20 individuals, 17 confirmed de novo (PMID:23815551). A separate cohort of 71 CSS patients identified ARID1B variants in 37 probands, supporting autosomal dominant inheritance (PMID:25081545). Case reports describe de novo nonsense mutations such as c.1924C>T (p.Gln642Ter) (PMID:36473251) and splice-site variants (c.5025+2T>C) leading to exon 19 skipping (PMID:31628733).

The variant spectrum is dominated by truncating alleles—nonsense and frameshift mutations—distributed throughout the coding sequence. Non-truncating missense variants are rare and typically escape nonsense-mediated decay. No recurrent or population-specific founder variants have been identified to date.

Functional studies support a loss-of-function mechanism. An iPSC line harboring c.1924C>T (p.Gln642Ter) maintained pluripotency and trilineage differentiation capacity while validating the pathogenic allele (PMID:36473251). Saturation mutagenesis revealed that pathogenic missense variants destabilize ARID1B protein, consistent with haploinsufficiency (PMID:38347147). Moreover, non-truncating variants in EHD2 and ARID domains cause cytoplasmic or nuclear aggregates in cell models, phenocopying haploinsufficiency via protein sequestration (PMID:39028335).

Collectively, these data delineate a haploinsufficiency mechanism in which loss of ARID1B disrupts SWI/SNF complex function, resulting in neurodevelopmental impairment. The consistent observation of de novo events and occasional familial transmission with variable expressivity confirms autosomal dominant inheritance.

ARID1B molecular testing should be pursued in individuals presenting with intellectual disability, hypertrichosis, sparse scalp hair, coarse facial features, and fifth-digit nail hypoplasia. Confirmatory genetic diagnosis facilitates recurrence risk counseling, informs prognosis, and may guide future chromatin-targeted therapeutic strategies.

References

• Stem cell research • 2023 • Establishment of an induced pluripotent stem cell (iPSC) line SDQLCHi045-A from peripheral blood mononuclear cells of a patient with Coffin-Siris syndrome 1 carrying a mutation in ARID1B gene. PMID:36473251
• Clinical genetics • 2014 • Coffin-Siris syndrome is a SWI/SNF complex disorder. PMID:23815551
• American journal of medical genetics. Part C, Seminars in medical genetics • 2014 • Numerous BAF complex genes are mutated in Coffin-Siris syndrome. PMID:25081545
• Molecular genetics & genomic medicine • 2019 • De novo splice site variant of ARID1B associated with pathogenesis of Coffin-Siris syndrome. PMID:31628733
• Nature structural & molecular biology • 2024 • Protein destabilization underlies pathogenic missense mutations in ARID1B. PMID:38347147
• Human genetics • 2024 • The missing link: ARID1B non-truncating variants causing Coffin-Siris syndrome due to protein aggregation. PMID:39028335
• European journal of human genetics : EJHG • 2014 • Coffin-Siris Syndrome with obesity, macrocephaly, hepatomegaly and hyperinsulinism caused by a mutation in the ARID1B gene. PMID:24569609

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