title: Sudden Cardiac Arrest and Rare Genetic Variants in the Community.
abstract: BACKGROUND
  Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored.
  
  
  RESULTS
  We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02).
  
  
  CONCLUSIONS
  This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community.
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Annalisa
authors.initials: A
authors.lastname: Milano
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Marieke T
authors.initials: MT
authors.lastname: Blom
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Lodder
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Daniel A
authors.initials: DA
authors.lastname: van Hoeijen
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Abdennasser
authors.initials: A
authors.lastname: Bardai
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Leander
authors.initials: L
authors.lastname: Beekman
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.). h.l.tan@amc.nl c.r.bezzina@amc.nl.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.affiliation: From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.). h.l.tan@amc.nl c.r.bezzina@amc.nl.
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
mesh_terms: D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000453:epidemiology / Q000209:etiology*; D005260:Female; D018703:Founder Effect; D014644:Genetic Variation; D005843:Geography; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D012111:Residence Characteristics
keywords: arrhythmia; cardiac arrest; founder mutations; genetics; population genetics