Original Investigation
Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome

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Abstract

Background

BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart.

Objectives

The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).

Methods

Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations.

Results

We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane.

Conclusions

Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

Key Words

Brugada syndrome
cardiac arrhythmias
cardiac conduction disease
electrophysiology
genetics
sudden cardiac death

Abbreviations and Acronyms

AF
atrial fibrillation
BrS
Brugada syndrome
CCD
cardiac conduction defect
Co-IP
coimmunoprecipitation
ECG
electrocardiogram
ERS
early repolarization syndrome
INa
sodium channel current
MAF
minor allele frequency
PRI
PR interval
RBBB
right bundle branch block
SCD
sudden cardiac death
VF
ventricular fibrillation
VT
ventricular tachycardia
WT
wild-type

Cited by (0)

This study was supported by the Masons of New York, Florida, Massachusetts, Connecticut, Maryland, Wisconsin, and Rhode Island. Drs. Hu and Barajas-Martínez were supported by Consejo Nacional de Ciencia y Tecnología (CONACYT; FM201866). Dr. Betzenhauser was supported by a National Research Service Award fellowship (F32-HL107029). Drs. Belardinelli, Kahlig, and Rajamani are employees of Gilead Sciences. Dr. DeAntonio is a speaker for Boehringer Ingelheim. Dr. Antzelevitch was supported by grants from the National Heart, Lung, and Blood Institute/National Institutes of Health (HL47678) and the New York Stem Cell Foundation (C026424); and is a paid consultant for Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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