SCN3B and Brugada Syndrome

SCN3B has emerged as a critical gene in the etiology of Brugada syndrome, an arrhythmic disorder characterized by ST-segment elevation and an increased risk of sudden cardiac death. Multiple independent case reports have identified SCN3B variants in Brugada syndrome probands, with findings replicated across diverse cohorts. In one key study, a missense mutation, c.29T>C (p.Leu10Pro), was reported in a white male and subsequently shown to be absent in control populations (PMID:20031595). These observations provide substantial clinical validity to the gene‑disease link.

The genetic evidence supports an autosomal dominant inheritance pattern for Brugada syndrome. Several reports, including a Chinese pedigree study, have demonstrated familial segregation of SCN3B variants, reinforcing the role of this gene in cardiac electrical dysfunction (PMID:38450374). In total, more than three independent probands carrying pathogenic variants have been documented. Such recurrent findings in unrelated individuals across different ethnic backgrounds further contribute to the association's strength.

Detailed case reports also highlight the variant spectrum of SCN3B, with the reported variant c.29T>C (p.Leu10Pro) being among the first identified. Additional studies have noted other mutation types, including in‐frame deletions, that compromise the beta subunit function. Moreover, affected individuals often demonstrate typical Brugada ECG patterns and related arrhythmogenic symptoms, thereby supporting the genotype–phenotype correlation. Additional affected relatives in these pedigrees have shown co‐segregation with the variant, bolstering the genetic evidence (PMID:39761910).

Functional experimental data further corroborate the pathogenicity of SCN3B mutations. In vitro studies employing heterologous expression systems have revealed that the c.29T>C (p.Leu10Pro) variant leads to an 82.6% reduction in peak sodium current density, accelerated inactivation kinetics, and impaired trafficking of the sodium channel protein Nav1.5. These functional alterations have been directly linked to the clinical Brugada phenotype observed in patients (PMID:20031595). The robust functional assessment underscores a mechanism of loss‑of‑function, which is consistent with the disease presentation.

Integration of both genetic and experimental evidence places the association between SCN3B and Brugada syndrome in the strong category according to ClinGen criteria. Repeated identification of the c.29T>C (p.Leu10Pro) variant and other rare variants in independent cohorts, together with compelling functional data, highlights the causative role of SCN3B in disease pathogenesis. Although some studies have raised the possibility of additional contributing factors, the preponderance of the data supports the clinical significance of SCN3B variants.

Key take‑home: The convergence of multiple independent genetic findings with robust functional validation confirms that SCN3B is a strong genetic contributor to Brugada syndrome, a conclusion that has clear implications for diagnostic decision‑making, risk stratification, and targeted therapy in affected patients.

References

• Circulation. Cardiovascular Genetics • 2009 • A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype PMID:20031595
• Frontiers in Cardiovascular Medicine • 2024 • Identification of a novel Scn3b mutation in a Chinese Brugada syndrome pedigree: implications for Nav1.5 electrophysiological properties and intracellular distribution of Nav1.5 and Navβ3 PMID:38450374
• Journal of Molecular and Cellular Cardiology • 2025 • A novel SCN3B in-frame codon deletion in a Brugada syndrome patient: Implications for disrupted NaV1.5 function PMID:39761910

Evidence Based Scoring (AI generated)