title: Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York. Electronic address: dianah@mmrl.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martínez
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Ryan
authors.initials: R
authors.lastname: Pfeiffer
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Fabio
authors.initials: F
authors.lastname: Dezi
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Jenna
authors.initials: J
authors.lastname: Pfeiffer
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Tapan
authors.initials: T
authors.lastname: Buch
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betzenhauser
authors.affiliation: Gilead Sciences, Fremont, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Gilead Sciences, Fremont, California.
authors.forename: Kristopher M
authors.initials: KM
authors.lastname: Kahlig
authors.affiliation: Gilead Sciences, Fremont, California.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.affiliation: East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: DeAntonio
authors.affiliation: University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Myerburg
authors.affiliation: Department of Cardiology, Showa University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Guthrie Clinic, Sayre, Pennsylvania.
authors.forename: Pramod
authors.initials: P
authors.lastname: Deshmukh
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mark
authors.initials: M
authors.lastname: Marieb
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of South Korea.
authors.forename: Gi-Byoung
authors.initials: GB
authors.lastname: Nam
authors.affiliation: Aurora Cardiovascular Services, Milwaukee, Wisconsin.
authors.forename: Atul
authors.initials: A
authors.lastname: Bhatia
authors.affiliation: Department of Cardiology, Ege University School of Medicine, Izmir, Turkey.
authors.forename: Can
authors.initials: C
authors.lastname: Hasdemir
authors.affiliation: Hôspital Cardiologique du Haut Lévêque, Université Bordeaux II, Pessac, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Haïssaguerre
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Veltmann
authors.affiliation: University Medical Centre Mannheim, German Centre for Cardiovascular Research, Heidelberg/Mannheim, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schimpf
authors.affiliation: University Medical Centre Mannheim, German Centre for Cardiovascular Research, Heidelberg/Mannheim, Mannheim, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.affiliation: Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sami
authors.initials: S
authors.lastname: Viskin
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York. Electronic address: ca@mmrl.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics*; D055815:Young Adult
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human
keywords: Brugada syndrome; cardiac arrhythmias; cardiac conduction disease; electrophysiology; genetics; sudden cardiac death