SMARCE1 – Coffin-Siris Syndrome

Coffin-Siris syndrome (CSS) is a congenital autosomal dominant neurodevelopmental disorder characterized by variable degrees of intellectual disability, coarse facial features, hypertrichosis, sparse scalp hair, hypoplastic fifth-digit nails, and growth delay. Pathogenic variants in genes encoding subunits of the SWI/SNF (BAF) chromatin-remodeling complex underlie CSS; among these, SMARCE1 (BAF57) is the least commonly implicated gene.

Initial exome sequencing in a cohort of 23 unrelated CSS patients identified a de novo missense SMARCE1 variant c.218A>G (p.Tyrosine73Cysteine) in one individual (PMID:22426308). An American Journal of Medical Genetics report described three additional unrelated cases with heterozygous deleterious SMARCE1 variants, doubling the known SMARCE1-related CSS cases to six (PMID:27264197). A larger registry study of 208 CSS patients subsequently identified one further SMARCE1-mutant case (PMID:34205270). In total, six unrelated probands with de novo SMARCE1 variants support a robust genetic association.

SMARCE1-related CSS follows an autosomal dominant inheritance pattern with all reported variants arising de novo; no evidence of germline transmission has been documented. Segregation analysis is limited to absence of variants in unaffected parents, underpinning the critical role of SMARCE1 haploinsufficiency or dominant-negative effects in pathogenesis.

The variant spectrum for SMARCE1 in CSS includes missense changes affecting highly conserved residues (e.g., c.218A>G (p.Tyrosine73Cysteine)) and predicted splicing defects. No recurrent or founder alleles have been observed. Clinical features in SMARCE1-mutant patients overlap broadly with other CSS genotypes, notably hypertrichosis (HP:0000998), coarse facial features (HP:0000280), sparse scalp hair (HP:0002209), and growth delay (HP:0001510).

Functional studies demonstrate that loss of SMARCE1 perturbs BAF complex activity: zebrafish smarce1 mutants display endocardial malformations and dysregulated cardiac transcription factor expression, recapitulating developmental defects (PMID:30337622). Neuron-specific splicing of BAF57 isoforms further confirms SMARCE1’s critical role in neural chromatin remodeling (PMID:19245665). These concordant in vivo and biochemical data substantiate the mechanistic link between SMARCE1 dysfunction and CSS phenotypes.

Collectively, the presence of six unrelated de novo SMARCE1 variants, consistent autosomal dominant inheritance, and model organism and molecular assays provide definitive evidence supporting SMARCE1 as a CSS-causing gene. Inclusion of SMARCE1 in diagnostic panels is warranted to enable accurate clinical diagnosis, genetic counseling, and tailored management.

References

• Nature Genetics • 2012 • Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. PMID:22426308
• American Journal of Medical Genetics Part A • 2016 • SMARCE1, a rare cause of Coffin-Siris Syndrome: Clinical description of three additional cases. PMID:27264197
• Genes • 2021 • Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome. PMID:34205270
• Scientific Reports • 2018 • smarce1 mutants have a defective endocardium and an increased expression of cardiac transcription factors in zebrafish. PMID:30337622
• Journal of Neurochemistry • 2009 • N-terminally truncated BAF57 isoforms contribute to the diversity of SWI/SNF complexes in neurons. PMID:19245665

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