Genotype-phenotype analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: Follow-up of a large series of dutch index-patients and family members

Moniek G.P.J. Cox, Paul A. Van Der Zwaag, Christian Van Der Werf, Jasper J. Van Der Smagt, Maartje Noorman, Zahir A. Bhuiyan, Ans C.P. Wiesfeld, Paul G.A. Volders, Irene M. Van Langen, Douwe E. Atsma, Dennis Dooijes, Arthur Van De Wijngaard, Arjan C. Houweling, Jan D.H. Jongbloed, Luc Jordaens, Maarten J. Cramer, Pieter A. Doevendans, Jacques M.T. De Bakker, Arthur A.M. Wilde, J. Peter Van TintelenRichard N.W. Hauer

Research output: Contribution to journalArticleAcademicpeer-review


Background: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) causative mutations in genes encoding 5 desmosomal proteins or TMEM43 are found in the majority of patients. One of the primary clinical challenges in ARVD/C is timely diagnosis of those still asymptomatic. However, previous studies mainly involved overt ARVD/C index-patients. Follow-up data on relatives are scarce. Therefore, we sequenced all 6 genes in a large cohort of ARVD/C families and correlated results with clinical follow-up. Methods: 149 ARVD/C index-patients (111 men, age 49±13 years) according to 2010 Task Force Criteria (TFC) and 302 family members from 93 different families (282 asymptomatic, 135 men, age 44±13 years) were clinically and genetically analyzed. DNA analysis comprised sequencing of PKP2, DSC2, DSG2, DSP, JUP and TMEM43 and multiple ligation-dependent probe amplification (MLPA) to identify large PKP2 deletions. Results: Pathogenic mutations were found in 87 of 149 index-patients (58%): 90% PKP2 and multiple mutations in 4 cases. MLPA revealed 3 large PKP2 deletions (2%). Mutation carriers presented at younger age than non-carriers (35±12 vs 40±14 years; p=0.042). Familial cases were identified in 42 of 93 (45%) of index-patients with relatives screened: 90% with mutations. In total, 57 of 282 asymptomatic relatives (20%) showed signs of ARVD/C (age 47±18 years, 48 with mutations). See table 2. Terminal activation duration (TAD) 7ge;55ms occurred more than negative T waves in V1-3 (12 vs 7%), especially in those aged
Original languageEnglish
Pages (from-to)1722-1723
Number of pages2
JournalHeart Rhythm
Issue number11
Publication statusPublished - Nov-2010


  • protein
  • DNA
  • heart electrophysiology
  • patient
  • follow up
  • genotype
  • phenotype
  • society
  • mutation
  • multiplex ligation dependent probe amplification
  • gene
  • diagnosis
  • DNA determination
  • T wave
  • sudden death
  • gene mutation

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