title: Arrhythmogenic right ventricular cardiomyopathy: implications of next-generation sequencing in appropriate diagnosis.
abstract: OBJECTIVE
  To evaluate potential differences in the genetic profile of cases with 'definite', 'borderline', and 'possible' arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype by 2010 task force criteria using a custom genetic panel after whole-exome analysis.
  
  
  RESULTS
  We performed whole-exome sequencing in 14 cases with the clinical diagnosis ARVC using an 'Illumina HighSeq 2000' system. We presented our initial results focused on 96 known cardiomyopathy and channelopathy genes. According to the 2010 task force criteria, 7/14 cases (50%) were classified as 'definite' phenotype, 4/14 (29%) were 'borderline', and 3/14 (21%) were diagnosed with the 'possible' phenotype. Nine out of 14 patients (64%) were males, and all were Caucasians, with an average age at genetic diagnosis of 50 ± 15 years. Among the seven cases with the 'definite' phenotype, six (86%) had a putative desmosomal mutation, while none of the seven patients with a 'possible' or borderline task force classification phenotype hosted putative mutations in desmosomal genes. Four (57%) of them had rare variants in other dilated cardiomyopathy (DCM) genes.
  
  
  CONCLUSIONS
  Most of the patients with 'definite' ARVC phenotype by task force 2010 host mutations in desmosomal genes. Weaker ARVC phenotypes host variants/mutations in other DCM genes and result in a disease spectrum, including DCM or phenocopies of ARVC.
authors.affiliation: Department of Cardiology, University Hospital Bern, 3010 Bern, Switzerland.
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: Ardan M
authors.initials: AM
authors.lastname: Saguner
authors.affiliation: Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.
authors.forename: István
authors.initials: I
authors.lastname: Magyar
authors.affiliation: Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Bahr
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: Deniz
authors.initials: D
authors.lastname: Akdis
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: Corinna
authors.initials: C
authors.lastname: Brunckhorst
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Firat
authors.initials: F
authors.lastname: Duru
authors.affiliation: Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.|Neuroscience Center Zurich (ZNZ), University and ETH Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D000073359:Exome Sequencing; D055815:Young Adult
chemical_list: D005819:Genetic Markers
keywords: Arrhythmogenic right ventricular cardiomyopathy; Cardiac channelopathies; Dilated cardiomyopathy; Next-generation sequencing; Whole-exome sequencing