SMARCA4 – Coffin-Siris syndrome

Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, coarse facial features, hypoplastic fifth digits and variable organ anomalies. The first SMARCA4-associated CSS case described a male patient harboring a novel de novo heterozygous missense variant, c.2434C>T (p.Leu812Phe), in motif Ia of the SNF2 domain, presenting evolving hypertonia and upper airway obstruction (PMID:24700502). Subsequent single-case reports have expanded the phenotype to include retinal dystrophy and microphthalmia, reflecting pleiotropy across organ systems (PMID:30973214; PMID:28608987).

Multi-patient exome sequencing in 23 individuals with CSS identified eight distinct de novo SMARCA4 variants, establishing SMARCA4 as one of six BAF complex genes mutated in 87% of screened cases (PMID:22426308). Larger cohorts confirmed SMARCA4 variants in ~11% of CSS patients, with clinical features often milder than those caused by other BAF genes and lacking marked facial coarseness (PMID:31530938).

All reported SMARCA4 variants in CSS occur de novo and exert autosomal dominant effects; no familial segregation has been observed. To date, 35 pathogenic SMARCA4 alleles have been reported in at least 32 unrelated probands, meeting criteria for a strong genetic association under ClinGen guidelines.

Functional studies support haploinsufficiency and dominant-negative mechanisms. A germline nonsense variant was shown to undergo nonsense-mediated decay and reduce SMARCA4 protein by ~50% in patient cells (PMID:28608987). Molecular modeling maps missense variants to DNA-binding regions and predicts disruption of chromatin remodeling, consistent with a dominant-negative impact on SWI/SNF function (PMID:31160358).

No studies have formally disputed the SMARCA4–CSS association. The convergence of de novo variant data, segregation absence, and concordant functional assays supports a robust gene–disease link.

In summary, heterozygous de novo SMARCA4 variants cause CSS via haploinsufficiency and dominant-negative disruption of SWI/SNF remodeling. Genetic testing for SMARCA4 is recommended in patients with CSS features, enabling accurate diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2014 • Coffin-Siris syndrome: phenotypic evolution of a novel SMARCA4 mutation. PMID:24700502
• Nature genetics • 2012 • Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. PMID:22426308
• Clinical genetics • 2019 • Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients. PMID:31530938
• The Journal of pathology • 2017 • SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type. PMID:28608987
• 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

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