SMARCA2 – Nicolaides-Baraitser Syndrome

Nicolaides-Baraitser syndrome (NCBRS; MONDO:0011053) is an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, sparse scalp hair, brachydactyly, prominent interphalangeal joints, and seizures. Pathogenic sequence variants in SMARCA2 (HGNC:11098), encoding the catalytic ATPase subunit of the SWI/SNF chromatin remodeling complex, underlie NCBRS and are predominantly de novo missense mutations clustered in the ATPase/helicase domain PMID:22366787.

Genetic evidence for SMARCA2-NCBRS is robust. Exome sequencing in ten individuals identified heterozygous SMARCA2 variants in eight patients, and targeted screening found nonsynonymous SMARCA2 mutations in 36 of 44 probands (Definitive; de novo in available trios) (PMID:22366787). Variants cluster in ultra-conserved motifs of the ATPase domain, including c.3451C>T (p.His1151Tyr), which recurs in multiple unrelated cases. Additional independent series include three patients with a de novo 32-kb in-frame deletion and two further missense cases in the C-terminal helicase domain (PMID:22822383).

Phenotypic spectrum and prevalence are informed by case reports and cohorts. Over 50 unrelated probands have been described across multiple studies, all harboring heterozygous SMARCA2 variants with consistent core features: moderate-to-severe intellectual disability (HP:0001249), sparse scalp hair (HP:0008070), brachydactyly (HP:0001156), and seizures (HP:0001250). A report of paternal germline mosaicism for c.553C>G (p.Gln185Glu) expands genetic transmission modes but underscores de novo dominance (PMID:34296532).

Functional studies support haploinsufficiency and dominant-negative mechanisms. Engineered hESCs carrying NCBRS-associated SMARCA2 K755R or R1159Q variants exhibit impaired differentiation into neural progenitors, enhancer reprogramming with loss of SOX3-dependent neural enhancers, and aberrant SMARCA4 retargeting (PMID:31375262). Moreover, genome-wide DNA methylation profiling of eight NCBRS cases identifies a 429-CpG signature mapping to neuronal and developmental genes, classifies VUS, and correlates with variant position in SMARCA2 (PMID:31288860).

Confounding evidence arises from variants outside the helicase domain causing a distinct blepharophimosis–intellectual disability syndrome (BIS), but these do not undermine the SMARCA2–NCBRS association, rather highlight domain-specific phenotypes (PMID:32694869). No studies refute SMARCA2’s role in NCBRS.

In summary, SMARCA2 heterozygous mutations cause NCBRS via dominant de novo ATPase domain variants, with extensive clinical, genetic, and experimental evidence meeting ClinGen criteria for a Definitive gene-disease relationship. SMARCA2 testing should be included in diagnostic panels for syndromic intellectual disability, and functional assays inform variant interpretation. Key take-home: de novo SMARCA2 ATPase mutations define NCBRS and guide diagnosis, management, and genetic counseling.

References

• Nature Genetics | 2012 | Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome PMID:22366787
• Molecular Syndromology | 2012 | In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome PMID:22822383
• Molecular Cell | 2019 | Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4 PMID:31375262
• BMC Medical Genomics | 2019 | New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome PMID:31288860
• Genetics in Medicine | 2020 | De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome PMID:32694869

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