SCN10A – Brugada Syndrome

Brugada syndrome (BrS) is an autosomal dominant arrhythmia characterized by ST-segment elevation in the right precordial leads and a high risk of ventricular tachyarrhythmias and sudden cardiac death. Although SCN5A mutations account for ~20% of cases, SCN10A, encoding the Nav1.8 sodium channel, has emerged as a significant contributor to BrS susceptibility through both common and rare variants. Identification of SCN10A variants in multiple independent cohorts supports its role as a BrS-predisposing gene.

Genetic evidence from cohort studies includes 25 BrS probands harboring SCN10A mutations, representing 16.7% of a 150-proband cohort (23 overlapping phenotypes) (PMID:24998131) and six additional SCN10A variant carriers (2.5% of 240 Japanese SCN5A/other-gene–negative probands) (PMID:25842276). Familial co-segregation of SCN10A variants has been documented in at least one pedigree (PMID:25691538), consistent with autosomal dominant inheritance.

The variant spectrum is dominated by missense changes clustering in transmembrane and cytoplasmic linker domains. A recurrent pathogenic allele, c.3749G>A (p.Arg1250Gln), has been reported in independent BrS patients (PMID:31106349). Functional null and hypomorphic alleles, including p.Arg1268Gln and p.R14Leu, together with common polymorphisms such as V1073A, underscore both rare-variant and common-variant contributions to disease.

Experimental studies demonstrate loss-of-function effects of SCN10A variants on sodium current. Human iPSC-derived cardiomyocytes carrying c.3749G>A (p.Arg1250Gln) exhibit reduced peak INa and altered gating (PMID:35448095), and heterologous coexpression of mutant Nav1.8 with Nav1.5 in HEK cells shows >80% current reduction for R14L and R1268Q (PMID:24998131). LPS-ROS-PKC–mediated exacerbation of Nav1.8 loss-of-function further implicates inflammation in BrS pathogenesis.

Mechanistically, SCN10A variants modulate Nav1.5 function via direct channel interaction and enhancer-mediated SCN5A expression, leading to slowed conduction and arrhythmia. Convergent data from genetic, cellular, and biophysical studies establish haploinsufficiency of Nav1.8 as a BrS mechanism.

Take-Home

SCN10A variants confer a strong, autosomal dominant predisposition to Brugada syndrome through loss-of-function effects on cardiac sodium current, supporting their inclusion in diagnostic panels and risk stratification.

References

• Journal of the American College of Cardiology • 2014 • Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome PMID:24998131
• Europace • 2016 • Novel SCN10A variants associated with Brugada syndrome PMID:25842276
• Europace • 2019 • A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes PMID:31106349
• Journal of Cardiovascular Development and Disease • 2022 • Lipopolysaccharide modifies sodium current kinetics through ROS and PKC signalling in induced pluripotent stem-derived cardiomyocytes from Brugada syndrome patient PMID:35448095

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