SCN5A – Paroxysmal Familial Ventricular Fibrillation

SCN5A encodes the α-subunit of the cardiac voltage-gated sodium channel (NaV1.5), a key determinant of impulse propagation in the heart. Pathogenic variants in SCN5A have been linked to a spectrum of arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3, conduction disease, and idiopathic ventricular fibrillation—termed paroxysmal familial ventricular fibrillation in MONDO (MONDO:0100234).

Genetic evidence for SCN5A in paroxysmal familial ventricular fibrillation includes at least six unrelated probands harboring heterozygous SCN5A variants presenting with idiopathic VF or early-repolarization–associated VF ([PMID:22028457], [PMID:32153684], [PMID:32063450], [PMID:37206574]). Variant classes span missense (e.g., c.677C>A (p.Ala226Asp)), splice-site, frameshift (e.g., c.839del (p.Cys280SerfsTer?)), and promoter variants, consistent with autosomal dominant inheritance.

Segregation data are limited. In one kindred, the pore-region variant p.Arg376Cys was identified in nine relatives, of whom two exhibited conduction abnormalities and sudden death, supporting variant pathogenicity ([PMID:15851228]).

Functional studies in heterologous systems demonstrate loss-of-function for idiopathic VF–associated SCN5A variants. The p.Ala226Asp mutant abolished sodium current and disrupted channel trafficking in 293 cells, while frameshift mutations such as p.Cys280SerfsTer? completely abrogated current, consistent with haploinsufficiency and slowed conduction ([PMID:22028457], [PMID:37206574]).

Mechanistically, reduced INa from SCN5A variants leads to conduction slowing and increased susceptibility to phase 2 reentry and VF. Concordant findings across patch-clamp, immunocytochemical, and cell-based models establish a causal link between NaV1.5 loss-of-function and paroxysmal familial ventricular fibrillation.

Key Take-home: Heterozygous SCN5A variants confer moderate evidence for autosomal dominant paroxysmal familial VF, and genetic testing of SCN5A should be considered in idiopathic VF cases to guide diagnosis and management.

References

• Circulation. Arrhythmia and Electrophysiology • 2011 • Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. PMID:22028457
• Journal of cardiology cases • 2020 • SCN5A mutation and a short coupled variant of Torsades de Pointes originating from the right ventricle: A case report. PMID:32153684
• Journal of clinical neuroscience • 2020 • Idiopathic ventricular fibrillation and the V1764fsX1786 frameshift mutation of the SCN5A gene in a myotonic dystrophy type 1 patient. PMID:32063450
• Experimental and therapeutic medicine • 2023 • Novel SCN5A frame-shift mutation underlying in patient with idiopathic ventricular fibrillation manifested with J wave in inferior lead and prolonged S-wave in precordial PMID:37206574
• 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

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