title: Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval.
abstract: OBJECTIVE
  We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers.
  
  
  RESULTS
  All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) and 95 of 5861 (1.6%) individuals, respectively, had experienced syncope during follow-up (P = 0.80). There was no significant difference in overall mortality rates between carriers [7/217 (3.2%)] and non-carriers [301/6453 (4.7%)] (P = 0.24).
  
  
  CONCLUSIONS
  We present QTc data and register data, indicating that 26 cLQTS-associated variants neither had any effect on the QTc intervals nor on syncope propensity or overall mortality. Based on the frequency of individual gene variants, we suggest that the 10 variants frequently identified, assumed to relate to cLQTS, are less likely to associate with a dominant monogenic form of the disease.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ghouse
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian Theil
authors.initials: CT
authors.lastname: Have
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Weeke
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bille Nielsen
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark.
authors.forename: Gustav
authors.initials: G
authors.lastname: Ahlberg
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Balslev-Harder
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Emil Vincent
authors.initials: EV
authors.lastname: Appel
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, Copenhagen, Denmark.
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.affiliation: Research Centre for Prevention and Health, The Capital Region, Copenhagen, Denmark Department of Clinical Experimental Research, Glostrup University Hospital, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark Department of Medicine and Surgery, Faculty of Health 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, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark Department of Medicine and Surgery, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Hastrup Svendsen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Laboratory of Experimental Cardiology, Department of Biomedicine, University of Copenhagen, Copenhagen, Denmark Department of Cardiology, Herlev and Gentofte University Hospitals, Copenhagen, Denmark.
authors.forename: Jørgen Kim
authors.initials: JK
authors.lastname: Kanters
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, University Hospital of Copenhagen, Rigshospitalet, 9312, Juliane Mariesvej 20, Copenhagen OE 2100, Denmark morten.salling.olesen@gmail.com.
authors.forename: Morten
authors.initials: M
authors.lastname: Salling Olesen
mesh_terms: D003718:Denmark / Q000453:epidemiology; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D006339:Heart Rate / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D008133:Long QT Syndrome / Q000151:congenital / Q000235:genetics* / Q000401:mortality; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012307:Risk Factors; D013575:Syncope / Q000235:genetics
chemical_list: D026901:Membrane Transport Proteins
keywords: Exome; False-positive variants; Human Gene Mutation Database; LQTS; Long QT syndrome