SCN5A – Dilated Cardiomyopathy

SCN5A encodes the cardiac sodium channel Nav1.5, crucial for impulse conduction and myocardial excitability. Rare missense and truncating SCN5A variants have been identified in patients with dilated cardiomyopathy (DCM), often presenting alongside arrhythmic phenotypes such as atrial fibrillation and ventricular tachycardia ([PMID:21596231]). Nav1.5 dysfunction can lead to disrupted conduction, arrhythmia, and secondary ventricular remodeling.

Clinical Validity

Overall Strength: Strong

Rationale: Multiple SCN5A variants in >10 unrelated DCM probands; familial segregation with conduction disease and arrhythmias; concordant functional data demonstrating altered sodium currents ([PMID:21596231], [PMID:15671429]).

Genetic Evidence

Inheritance Mode: Autosomal dominant

Segregation: 14 affected relatives with segregating variants confirmed across 9 families ([PMID:21596231]).

Case Series: Eight unrelated DCM probands harbored five missense (e.g., p.Arg222Gln) and two truncating variants. Population screening showed SCN5A mutations in ~1.7% of DCM families ([PMID:21596231]).

Variant Spectrum: Predominantly missense substitutions in voltage-sensing and pore domains; frameshift/truncating alleles rare but observed (e.g., c.2550_2551dup).

Prevalence: SCN5A mutations account for ~2–4% of genetic DCM cases, enriched in familial cohorts ([PMID:15671429]).

Functional Evidence

Mechanism: Mixed gain- and loss-of-function defects leading to altered window currents, gating pore leaks, and reduced peak INa.

Key Assays: Xenopus oocyte and HEK293 patch-clamp studies demonstrate reduced peak current density and gating shifts for R225H and R814W variants ([PMID:22675453]); heart-on-a-chip models of R222Q-SCN5A recapitulate DCM-like contractile deficits; quinidine rescue of R222Q current and clinical phenotype ([PMID:29871609]).

Rescue Experiments: Sodium channel blockers (quinidine, flecainide) normalize ectopic burden and improve ventricular function in carriers of gain-of-function SCN5A variants.

Conflicting Evidence

A systematic review notes that DCM does not occur in the absence of arrhythmia for SCN5A variants and that truly DCM-specific SCN5A genotypes are rare, advocating careful interpretation in genotype-negative arrhythmic DCM ([PMID:34949099]).

Integration & Clinical Utility

SCN5A variants disrupt Nav1.5 gating, predisposing carriers to arrhythmias that drive ventricular dilation and systolic dysfunction. Genetic testing for SCN5A in familial DCM with prominent arrhythmic features guides targeted use of sodium channel blockaders and informs risk stratification. While additional variant–phenotype correlations continue to emerge, current evidence supports SCN5A as a strong but pleiotropic DCM gene.

Key Take-home: In autosomal dominant DCM with arrhythmias, SCN5A testing can identify actionable variants for genotype-directed therapy and familial risk assessment.

References

• Journal of the American College of Cardiology • 2011 • SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. PMID:21596231
• JAMA • 2005 • Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. PMID:15671429
• PLoS One • 2012 • A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype. PMID:22675453
• BMC Medical Genetics • 2018 • Rapid and effective response of the R222Q SCN5A to quinidine treatment in a patient with Purkinje-related ventricular arrhythmia and familial dilated cardiomyopathy: a case report. PMID:29871609
• Circulation: Genomic and Precision Medicine • 2022 • Arrhythmic Phenotypes Are a Defining Feature of Dilated Cardiomyopathy-Associated SCN5A Variants: A Systematic Review. PMID:34949099

Evidence Based Scoring (AI generated)