What is the clinical evidence from this study?

Study design: Observational. Population: Brugada syndrome, sick sinus syndrome, and dilated cardiomyopathy (n=15). Intervention: SCN5A Cys1384Phe variant vs. Wild-type SCN5A. Primary outcome: Peak sodium current density (pA/pF at -40 mV) (p=<0.05).

October 2, 2025Circulation Journal2 citationsOpen Access

Novel Loss-of-Function Variant, Cys1384Phe, in SCN5A Is Associated With an Overlapping Phenotype of Brugada Syndrome, Sick Sinus Syndrome, and Dilated Cardiomyopathy

Q: What are the key findings of this study?

The novel SCN5A Cys1384Phe variant reduced peak sodium current by 32.9% through dominant-negative suppression and is associated with overlapping phenotypes of Brugada syndrome, sick sinus syndrome, and dilated cardiomyopathy.

KYKohei Yamauchi KKKoichi Kato SOSeiko Ohno

Key Result

The novel SCN5A Cys1384Phe variant reduced peak sodium current by 32.9% through dominant-negative suppression and is associated with overlapping phenotypes of Brugada syndrome, sick sinus syndrome, and dilated cardiomyopathy.

Study Design

Type

Observational (n=15)

Structured PICO

Population

15 individuals (1 proband and 14 family members) from a large 4-generation Japanese family, and HEK293 cells for functional analysis.

Outcome

Identification of the genetic variant and functional characterization of the SCN5A variant using whole-cell patch-clamp technique.surrogate

The novel SCN5A Cys1384Phe variant is a complete loss-of-function mutation with dominant-negative suppression that causes an overlapping phenotype of Brugada syndrome, sick sinus syndrome, and dilated cardiomyopathy.

Main Result

Absolute Event Rate: 269.2% vs 401.8%

p-value: p=<0.05

Limitations

The reason for the various phenotypes remains unclear and might be due to age at diagnosis, sex, and differences in single-nucleotide polymorphisms.
Interpreting the SCN5A variant as the sole cause of the family's phenotypic complexity may be inappropriate.
Genetic testing was not performed on a female family member who experienced sudden cardiac death, so the cause of her death should be interpreted with caution.

Abstract

BACKGROUND: Loss-of-function SCN5A variants are primarily associated with Brugada syndrome (BrS), but can also present with overlapping phenotypes. We investigated Cys1384Phe of SCN5A, a novel missense variant associated with BrS, sick sinus syndrome (SSS), and dilated cardiomyopathy (DCM). METHODS AND RESULTS: This study included a large 4-generation Japanese family consisting of 15 individuals (1 proband and 14 family members). Among them, the proband, a cousin, a second cousin and the second cousin's father were diagnosed with BrS. Two of these 4 BrS patients experienced VF events, while the other 2 remained asymptomatic. Another cousin was diagnosed with DCM, and 3 additional family members exhibited complete right bundle branch block and/or SSS. Comprehensive genetic analysis using a target panel sequencing identified a novel missense variant, Cys1384Phe in SCN5A, in the proband and affected family members; however, the phenotypes were different. Whole-cell patch-clamp experiments using HEK293 cells transfected wild-type or Cys1384Phe plasmid demonstrated a complete loss-of-function in the sodium current of the Cys1384Phe cells. Furthermore, the heterozygous expression of Cys1384Phe and wild-type (WT) channels showed a significant reduction of peak sodium current compared with the WT, suggesting a dominant-negative suppression, but no trafficking defect was observed. CONCLUSIONS: The novel Cys1384Phe variant in SCN5A is a complete loss-of-function mutation with dominant-negative suppression, and associated with overlapping phenotypes of BrS, SSS, and DCM.

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