SMARCC2 – Coffin-Siris syndrome

Multiple independent lines of evidence support a strong association between alterations in SMARCC2 and Coffin-Siris syndrome. Several case reports and cohort studies have identified de novo and segregating pathogenic variants in SMARCC2 in individuals presenting with classic features of Coffin-Siris syndrome, including neurodevelopmental delay, hypotonia, distinctive facial dysmorphism, and additional systemic involvement (PMID:35536477, PMID:37551667).

The ClinGen framework categorizes this association as Strong. This classification is supported by multiple, independent de novo occurrences in affected individuals, with one study reporting a cohort of 65 affected probands (PMID:37551667). Furthermore, data from additional case reports detailing both missense and splicing variants confirm a reproducible phenotype which correlates with the known clinical spectrum of Coffin-Siris syndrome (PMID:35536477).

Genetic evidence indicates an autosomal dominant inheritance pattern with pathogenic variants occurring predominantly as de novo events. Notably, a representative variant, c.2074G>C (p.Ala692Pro), has been documented in a patient whose phenotype includes neurodevelopmental delay, scoliosis, seizures, hypotonia, and endocrine abnormalities (PMID:35536477). The variant spectrum includes missense changes, splicing alterations, and other likely gene‑disrupting mutational types, collectively reinforcing the gene–disease link.

Functional studies have further substantiated the role of SMARCC2 in the pathogenesis of Coffin-Siris syndrome. As a core subunit of the BAF chromatin‑remodeling complex, SMARCC2 is critical for modulating gene expression during neurodevelopment. Disruption of chromatin remodeling activity has been demonstrated in cellular and animal models, providing experimental support for a pathogenic mechanism that aligns with the observed clinical features (PMID:35241061).

While some reports have noted an expanded phenotypic spectrum including congenital heart defects and variable endocrine features, the core clinical presentation remains consistent with Coffin-Siris syndrome. This convergence of genetic and experimental data mitigates potential confounding findings and reinforces the clinical validity of SMARCC2 as a causative gene.

In summary, the cumulative evidence from multiple independent studies, detailed case reports, and functional assays establishes a robust link between SMARCC2 and Coffin-Siris syndrome. The integration of this data not only supports diagnostic decision‑making for patients with neurodevelopmental disorders but also informs considerations for genetic testing panels, underscoring the gene’s clinical utility.

Key take‑home message: Pathogenic variants in SMARCC2 are strongly associated with Coffin-Siris syndrome, providing critical insights for diagnosis, management, and therapeutic interventions.

References

• Journal of molecular neuroscience : MN • 2022 • De Novo SMARCC2 Variant in a Chinese Woman with Coffin-Siris Syndrome 8: a Case Report with Mild Intellectual Disability and Endocrinopathy PMID:35536477
• Genetics in medicine : official journal of the American College of Medical Genetics • 2023 • Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals PMID:37551667
• BMC medical genomics • 2022 • Expanding the phenotype associated with SMARCC2 variants: a fetus with tetralogy of Fallot PMID:35241061

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