SCNN1A – Brugada syndrome

SCNN1A, encoding the α-subunit of the epithelial sodium channel (ENaC), has been implicated as a minor gene in Brugada syndrome (BrS), an autosomal dominant arrhythmogenic disorder associated with sudden cardiac death (PMID:30821013). Disease-targeted sequencing in 15 unrelated, non-familial BrS patients without SCN5A variants identified two SCNN1A de novo variants in two unrelated probands: c.1789C>T (p.Arg597Ter) and c.1049G>A (p.Arg350Gln), each confirmed by Sanger sequencing (PMID:25339316). No additional familial segregation has been reported. Clinical presentations in carriers included sudden cardiac death (HP:0001645) and syncope (HP:0001279).

A recent comprehensive review classified SCNN1A among four minor BrS genes harboring definitively pathogenic variants, reinforcing its potential role in BrS pathogenesis despite the absence of BrS-specific functional assays (PMID:30821013). In silico predictions support deleterious effects of the identified variants, but electrophysiological studies in relevant models are lacking. Further functional validation is needed to delineate the mechanism and to guide clinical decision-making.

Key take-home: SCNN1A variants have been observed de novo in unrelated BrS probands, providing limited genetic evidence; targeted functional studies are essential to confirm clinical utility.

References

• Scientific Reports • 2014 • Disease-targeted sequencing of ion channel genes identifies de novo mutations in patients with non-familial Brugada syndrome. PMID:25339316
• Human mutation • 2019 • Genetic interpretation and clinical translation of minor genes related to Brugada syndrome. PMID:30821013

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