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Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel α subunit Na V 1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel β1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, β1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when Na V 1.5 was coexpressed with mutant β1 or β1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.

Sudden cardiac death † J wave † Brugada syndrome † Early repolarization syndrome † Cardiac arrhythmia † Ventricular fibrillation † Inherited cardiac arrhythmia syndrome The consensus conference was organized with the assistance of the Chinese Heart Rhythm Society and funded by an unrestricted educational grant from Buchang Pharmaceuticals.

Objectives The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). Background BrS is an inherited sudden cardiac death syndrome. Fewer 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. Methods Clinical analysis and direct sequencing of BrS-susceptibility genes were performed on 150 probands, family members and >200 healthy controls. Expression and co-immunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. Results We identified 17 SCN10A mutations in 25 probands (20 M/5 F); 23 of the 25 (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). BrS patients with SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals than SCN10A negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous co-expression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current (INa) compared with WT-SCN5A alone. In contrast, co-expression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in INa, respectively. Co-immunoprecipitation studies performed provide evidence for co-association of Nav1.8 and Nav1.5 in the plasma membrane. Conclusions Our study identifies SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

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