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

WOS: 000339337700011PubMed ID: 24998131BACKGROUND 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 Na(v)1.8, 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 Na(v)1.8 and Na(v)1.5 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. (C) 2014 by the American College of Cardiology Foundation.Masons of New York; Florida; Massachusetts; Connecticut; Maryland; Wisconsin; Rhode Island; Consejo Nacional de Ciencia y Tecnologia (CONACYT)Consejo Nacional de Ciencia y Tecnologia (CONACyT) [FM201866]; National Research Service Award fellowshipUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [F32-HL107029]; National Heart, Lung, and Blood Institute/National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [HL47678]; New York Stem Cell Foundation [C026424]This study was supported by the Masons of New York, Florida, Massachusetts, Connecticut, Maryland, Wisconsin, and Rhode Island. Drs. Hu and Barajas-Martinez were supported by Consejo Nacional de Ciencia y Tecnologia (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