SMARCC2 – Coffin-Siris syndrome 8

BAFopathies are a group of neurodevelopmental disorders caused by variants in subunits of the BAF chromatin-remodeling complex. Heterozygous pathogenic variants in SMARCC2 have been linked to Coffin-Siris syndrome 8 (MONDO:0032702), a rare autosomal dominant neurodevelopmental disorder characterized by developmental delays, hypotonia, seizures, short stature and craniofacial anomalies. The SMARCC2 gene (SMARCC2) encodes the BAF170 subunit, crucial for chromatin remodeling and neurogenesis.

Genetic evidence includes a cohort of 65 affected individuals (41 novel and 24 published) harboring SMARCC2 variants with predominantly de novo occurrence and consistent clinical features (PMID:37551667). Two unrelated probands were identified with a de novo in-frame deletion, c.1824_1826del (p.Leu609del) (PMID:34881817), and a frameshift variant c.1094_1097delAGAA (p.Lys365ThrfsTer12) in an adopted subject. Additional reports include a prenatal case with c.3561del (p.Leu1188fs) and an adult with a missense c.2074G>C (p.Ala692Pro) (PMID:35241061; PMID:35536477). The spectrum spans loss-of-function, missense, splice and in-frame variants without clear genotype-phenotype correlations.

Functional studies support haploinsufficiency and dominant-negative effects. In vitro 3D modeling, co-immunoprecipitation and proximity-ligation assays showed reduced SMARCC2 protein expression and disrupted interactions with BRG1 in cells expressing N-terminal missense variants (PMID:37551667). A novel splice variant (c.1496+1G>T) was shown by RT-PCR and TA-clone sequencing to produce aberrant in-frame insertions and deletions, altering α-helix structure (PMID:39901255). The Evf2 lncRNA study in mouse forebrain identified SMARCC2 within the BAF complex and demonstrated RNA-dependent inhibition of chromatin remodeling, implicating SMARCC2 dysfunction in neurodevelopment (PMID:26138476).

No conflicting evidence has been reported that refutes the role of SMARCC2 in CSS8. All studies consistently observed de novo variants with overlapping neurodevelopmental phenotypes. Some LGD variants exhibit milder cognitive effects when inherited, but de novo non-truncating variants often present with severe delays, supporting a spectrum of dominant pathogenic mechanisms.

Collectively, the convergence of robust genetic data—over 65 unrelated probands with recurrent de novo variants—and concordant functional assays establishes a strong gene–disease relationship according to ClinGen. Further research into variant-specific mechanisms may refine genotype-phenotype correlations but exceeds the current scoring framework.

Key take-home: Heterozygous SMARCC2 variants cause autosomal dominant Coffin-Siris syndrome 8 with consistent neurodevelopmental phenotypes and supportive functional evidence, informing molecular diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2022 • Further supporting SMARCC2-related neurodevelopmental disorder through exome analysis and reanalysis in two patients. PMID:34881817
• BMC medical genomics • 2022 • Expanding the phenotype associated with SMARCC2 variants: a fetus with tetralogy of Fallot. PMID:35241061
• 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
• Development (Cambridge, England) • 2015 • Evf2 lncRNA/BRG1/DLX1 interactions reveal RNA-dependent inhibition of chromatin remodeling. PMID:26138476
• Orphanet journal of rare diseases • 2025 • Identification and functional analysis of a novel SMARCC2 splicing variant in a family with syndromic neurodevelopmental disorder. PMID:39901255

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