SCN5A – Brugada syndrome

Brugada syndrome is an autosomal dominant arrhythmia characterized by ST-segment elevation in the right precordial leads (V1–V3) and predisposition to ventricular fibrillation and sudden cardiac death. The SCN5A gene (HGNC:10593) encodes the Nav1.5 cardiac sodium channel, critical for phase 0 depolarization. Pathogenic SCN5A variants reduce inward Na⁺ current (I_Na), leading to loss of function and the Brugada ECG phenotype.

Clinical Validity

A definitive gene–disease association is established between SCN5A and Brugada syndrome. Over 2,111 unrelated Brugada probands were screened, identifying 438 distinct SCN5A variants (21% yield) (PMID:20129283). Multiple segregation studies, including five affected relatives with the p.Gly752Arg variant in a French kindred (PMID:12693506) and nine carriers of p.Arg376His in a European family (PMID:15851228), support autosomal dominant inheritance and high clinical validity.

Genetic Evidence

Inheritance is autosomal dominant with incomplete penetrance. Segregation analysis across families shows at least 14 affected relatives harboring pathogenic SCN5A variants. Case series report 438 probands with heterogeneous variant classes—predominantly missense, with nonsense, frameshift, splice, and deep-intronic changes—distributed across all four channel domains. Recurrent variants (e.g., c.2254G>C (p.Gly752Arg)) have been observed in multiple populations. The overall mutation spectrum underscores a strong genetic contribution (PMID:20129283).

Functional Evidence

Functional assays in heterologous systems demonstrate loss-of-function through reduced current density, hyperpolarizing shifts of inactivation, and accelerated inactivation kinetics for several mutants. The p.Gly752Arg mutant shows markedly decreased I_Na in patch-clamp studies (PMID:12693506), whereas the p.Gly1742Arg trafficking-defective mutant can be rescued by mexiletine (PMID:15023552). Concordant findings across tsA201, HEK-293, and Xenopus oocyte models reinforce the pathogenic mechanism of sodium channel haploinsufficiency.

Conflicting Evidence

Approximately one third of Brugada syndrome cases lack SCN5A variants (PMID:11960580), indicating genetic heterogeneity. A common polymorphism, p.His558Arg, modulates channel function and may influence clinical expressivity, improving I_Na and ECG parameters in mutation carriers (PMID:19549036).

Integration & Clinical Utility

SCN5A loss-of-function variants cause Brugada syndrome through impaired Nav1.5 channel gating or trafficking. Genetic testing for SCN5A variants is recommended for diagnosis, risk stratification, and guiding phenotype-directed therapies, including sodium channel blockers. Recognizing SCN5A mutations enables early family screening and may inform preventive strategies for sudden cardiac death.

Key Take-home: Pathogenic SCN5A variants definitively underlie Brugada syndrome and are essential biomarkers for diagnosis and management.

References

• Heart rhythm • 2010 • An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing PMID:20129283
• Journal of cardiovascular electrophysiology • 2003 • Novel brugada SCN5A mutation leading to ST segment elevation in the inferior or the right precordial leads. PMID:12693506
• Cardiovascular research • 2004 • A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. PMID:15023552
• Heart rhythm • 2004 • Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death. PMID:15851228
• Genetic testing • 2001 • Genetic analysis of Brugada syndrome in Israel: two novel mutations and possible genetic heterogeneity. PMID:11960580
• Journal of cardiovascular electrophysiology • 2009 • Genetic modulation of brugada syndrome by a common polymorphism. PMID:19549036

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