title: Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality.
abstract: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers.
  
  
  
  All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries.
  
  
  
  In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63-1.4).
  
  
  
  Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS.Genet Med advance online publication 06 October 2016.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ghouse
authors.affiliation: The Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian T
authors.identifier: 0000-0002-8634-4781
authors.initials: CT
authors.lastname: Have
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.
authors.forename: Morten W
authors.initials: MW
authors.lastname: Skov
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.
authors.forename: Laura
authors.initials: L
authors.lastname: Andreasen
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.
authors.forename: Gustav
authors.identifier: 0000-0003-0066-2779
authors.initials: G
authors.lastname: Ahlberg
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.|Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jonas B
authors.identifier: 0000-0002-6654-2852
authors.initials: JB
authors.lastname: Nielsen
authors.affiliation: Research Centre for Prevention and Health, The Capital Region, Copenhagen, Denmark.
authors.forename: Tea
authors.initials: T
authors.lastname: Skaaby
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.affiliation: The Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.identifier: 0000-0001-5526-1070
authors.initials: N
authors.lastname: Grarup
authors.affiliation: Research Centre for Prevention and Health, The Capital Region, Copenhagen, Denmark.|Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Allan
authors.identifier: 0000-0002-0994-0184
authors.initials: A
authors.lastname: Linneberg
authors.affiliation: The Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: The Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik
authors.identifier: 0000-0003-3090-269X
authors.initials: H
authors.lastname: Vestergaard
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.affiliation: The Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jørgen K
authors.identifier: 0000-0002-3267-4910
authors.initials: JK
authors.lastname: Kanters
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.|Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, Denmark.
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000453:epidemiology* / Q000209:etiology; D053840:Brugada Syndrome / Q000150:complications / Q000235:genetics* / Q000401:mortality* / Q000503:physiopathology; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011897:Random Allocation; D012042:Registries; D013575:Syncope / Q000453:epidemiology* / Q000209:etiology; D000073359:Exome Sequencing / Q000379:methods