title: Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers.
abstract: OBJECTIVE
  We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers.
  
  
  RESULTS
  Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs. 36 years; P < 0.001) than those presenting with sustained monomorphic ventricular tachycardia (VT). Among 541 subjects presenting alive, over a mean follow-up of 6 ± 7 years, 12 (2%) patients died, 162 (30%) had sustained VT/VF, 78 (14%) manifested left ventricular dysfunction (EF < 55%), 28 (5%) experienced heart failure (HF), and 10 (2%) required cardiac transplantation. Patients (n = 22; 4%) with >1 mutation had significantly earlier occurrence of sustained VT/VF (mean age 28 ± 12 years), lower VT-/VF-free survival (P = 0.037), more frequent left ventricular dysfunction (29%), HF (19%) and cardiac transplantation (9%) when compared with those with only one mutation. Desmoplakin mutation carriers experienced more than four-fold occurrence of left ventricular dysfunction (40%) and HF (13%) than PKP2 carriers. Missense mutation carriers had similar death-/transplant-free survival and VT/VF penetrance (P = 0.137) when compared with those with truncating or splice site mutations. Men are more likely to be probands (P < 0.001), symptomatic (P < 0.001) and have earlier and more severe arrhythmic expression.
  
  
  CONCLUSIONS
  Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bhonsale
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands Interuniversity Cardiology Institute of the Netherlands (ICIN), PO Box 19258, 3501 DG Utrecht, The Netherlands.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Groeneweg
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: James
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Tichnell
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan D H
authors.initials: JD
authors.lastname: Jongbloed
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Brittney
authors.initials: B
authors.lastname: Murray
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Anneline S J M
authors.initials: AS
authors.lastname: te Riele
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Hennie
authors.initials: H
authors.lastname: Bikker
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Douwe E
authors.initials: DE
authors.lastname: Atsma
authors.affiliation: Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Natasja M
authors.initials: NM
authors.lastname: de Groot
authors.affiliation: Department of Genetics, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Houweling
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: van der Heijden
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Russell
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.affiliation: Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Toon A
authors.initials: TA
authors.lastname: van Veen
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tandri
authors.affiliation: Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Interuniversity Cardiology Institute of the Netherlands (ICIN), PO Box 19258, 3501 DG Utrecht, The Netherlands Durrer Center for Cardiogenetic Research, Utrecht, The Netherlands.
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Calkins
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands Interuniversity Cardiology Institute of the Netherlands (ICIN), PO Box 19258, 3501 DG Utrecht, The Netherlands r.n.w.hauer@umcutrecht.nl.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Hauer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000401:mortality; D016757:Death, Sudden, Cardiac / Q000209:etiology; D051301:Desmoglein 2 / Q000235:genetics; D051184:Desmoglein 3 / Q000235:genetics; D051182:Desmogleins / Q000235:genetics*; D051180:Desmoplakins / Q000235:genetics; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D051191:Plakophilins / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D055815:Young Adult; D051185:gamma Catenin
chemical_list: C495314:DSG2 protein, human; C071894:DSG3 protein, human; C495294:DSP protein, human; D051301:Desmoglein 2; D051184:Desmoglein 3; D051182:Desmogleins; D051180:Desmoplakins; C495292:JUP protein, human; C495337:PKP2 protein, human; D051191:Plakophilins; D051185:gamma Catenin
keywords: Arrhythmia; Arrhythmogenic right ventricular dysplasia/cardiomyopathy; Genetics; Prognosis