SMARCA4 – Intellectual disability, autosomal dominant 16

Coffin-Siris syndrome 4, classified as Intellectual disability, autosomal dominant 16, is an autosomal dominant neurodevelopmental disorder caused by heterozygous variants in SMARCA4, featuring moderate intellectual disability, global developmental delay, and sensorineural hearing impairment (PMID:32903985).

A young woman with moderate intellectual disability, developmental delay, and bilateral sensorineural hearing loss was found by high-resolution chromosomal microarray to harbor a 428 kb deletion encompassing SMARCA4, supporting haploinsufficiency as a disease mechanism (PMID:32903985).

In a cohort of 49 CSS-suspected patients, pathogenic non-truncating SMARCB1, SMARCA4, and ARID1B variants were identified in 20 individuals, with 17 confirmed as de novo by parental testing; all SMARCA4 alterations were missense or in-frame events consistent with dominant inheritance (PMID:23815551).

A separate case reported a novel de novo SMARCA4 missense variant, c.2647G>A (p.Gly883Ser), in a patient with CSS and severe congenital heart disease; molecular modeling localized the substitution to a DNA-binding domain, suggesting a dominant-negative effect on ATPase activity (PMID:31160358).

Functional studies of Brg1 hypomorphic alleles in mouse demonstrate that reduced SWI/SNF ATPase activity recapitulates multi-system developmental defects, underscoring SMARCA4 dosage sensitivity and concordance with human phenotypes (PMID:16287714).

Together, these data establish that heterozygous SMARCA4 loss-of-function and hypomorphic variants cause autosomal dominant intellectual disability, with consistent de novo occurrence and mechanistic support from animal models. Key Take-home: SMARCA4 haploinsufficiency reliably diagnoses Intellectual disability, autosomal dominant 16 and informs genetic counseling and targeted therapeutic development.

References

• Molecular syndromology • 2020 • Coffin-Siris Syndrome 4-Related Spectrum in a Young Woman Caused by a Heterozygous SMARCA4 Deletion Detected by High-Resolution aCGH. PMID:32903985
• Clinical genetics • 2014 • Coffin-Siris syndrome is a SWI/SNF complex disorder. PMID:23815551
• Cold Spring Harbor molecular case studies • 2019 • A case of Coffin-Siris syndrome with severe congenital heart disease and a novel SMARCA4 variant. PMID:31160358
• Genes & development • 2005 • A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in beta-globin expression and erythroid development. PMID:16287714

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