Key result
Loss-of-function SCN5A pore variants link to Brugada syndrome, whereas terminal variants remain largely asymptomatic.
Why the study?
Loss-of-function SCN5A variants cause various arrhythmia and conduction phenotypes, and auto-patch clamp technology now enables functional assessment of missense variants. However, the associations between specific loss-of-function missense SCN5A variants and the resulting phenotypes and disease severities in carriers had not yet been elucidated.
Cohort (n=128)
Phenotypic expression and disease severity in carriers of loss-of-function missense SCN5A variants vary substantially by channel location, with pore region variants associated with Brugada syndrome and severe events (cardiac arrest or syncope), highlighting the need for variant-specific risk stratification.
Answers are grounded in this paper and cite their sources.
May refine SCN5A carrier risk stratification by variant domain; leaves open prospective validation before guiding practice.
Background Loss-of-function (LOF) SCN5A variants cause various phenotypes, including Brugada syndrome (BrS), conduction disturbances, sick sinus syndrome (SSS), atrial arrhythmias, and others. Recent progress in the auto-patch clamp system has enabled us to evaluate functional changes in variants and determine the pathogenesis of missense variants. However, the associations between each missense variant and the phenotypes of variant carriers have not yet been elucidated. Objective We aimed to clarify the association between LOF-type missense SCN5A variants and phenotypes, including disease severities related to these variants. Methods The study cohort comprised 133 carriers of LOF-type missense SCN5A variants from 71 families. Their phenotypes were classified into BrS, SSS, atrioventricular block (AVB), atrial arrhythmias, and others. Detected variants were classified by channel location. Results In 133 carriers, 5 carriers with biallelic variants were excluded from the analysis. The age of the remaining 128 carriers at genetic testing was 29.5 [25.5-33.5] years, and 68 (53.1%) were male. The carrier numbers of each phenotype were n=60 in BrS, n=35 in SSS, n=18 in AVB, n=11 in atrial arrhythmias, and n=20 in other phenotypes. Overlapped phenotypes were observed in 24 carriers. Fifty LOF missense variants were detected in our cohort. Phenotypes in each variant are displayed in Figure 1. In 60 variant carriers with BrS, variants were highly observed in pore regions, especially at R893C/H (n=10) (domain II) and G1743R (n=7) (domain IV). In contrast, the number of variant carriers in domain III was similar in BrS (n=17) and SSS (n=14). Only 1 of 11 carriers with D1275N in the transmembrane region of domain III showed a BrS phenotype, and the remaining 11 showed bradyarrhythmia without a BrS phenotype. Figure 2 shows the locations of variants associated with cardiac arrest or syncope, with most variants located in pore regions. Carriers with variants in N- or C-terminal were asymptomatic. Conclusion Phenotypes and disease severity vary by location, even among the same LOF-type missense SCN5A variants. We need to evaluate the phenotypic and prognostic features of variant carriers for each SCN5A variant.
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Ohno et al. (2026) conducted a cohort in Loss-of-function missense SCN5A variants (Brugada syndrome, sick sinus syndrome, atrioventricular block, atrial arrhythmias) (n=128). Loss-of-function type missense SCN5A variants classified by channel location vs. Variant channel locations (pore regions, domains I-IV, N- or C-terminal) was evaluated on Phenotypic classification (Brugada syndrome, sick sinus syndrome, atrioventricular block, atrial arrhythmias) and disease severity (cardiac arrest or syncope). Loss-of-function missense SCN5A variants in 128 carriers caused Brugada syndrome (n=60) and sick sinus syndrome (n=35), with pore variants linked to BrS and N-/C-terminal variants asymptomatic.
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