Distinguishing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia-Associated Mutations From Background Genetic Noise

Jamie D. Kapplinger, Andrew P. Landstrom, Benjamin A. Salisbury, Thomas E. Callis, Guido D. Pollevick, David J. Tester, Moniek G. P. J. Cox, Zahir Bhuiyan, Hennie Bikker, Ans C. P. Wiesfeld, Richard N. W. Hauer, J. Peter van Tintelen, Jan D. H. Jongbloed, Hugh Calkins, Daniel P. Judge, Arthur A. M. Wilde, Michael J. Ackerman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

207 Citations (Scopus)

Abstract

Objectives The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result.

Background ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test.

Methods Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database.

Results The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2.

Conclusions This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation. (J Am Coll Cardiol 2011;57:2317-27) (C) 2011 by the American College of Cardiology Foundation

Original languageEnglish
Pages (from-to)2317-2327
Number of pages11
JournalJournal of the American College of Cardiology
Volume57
Issue number23
DOIs
Publication statusPublished - 7-Jun-2011

Keywords

  • arrhythmogenic right ventricular cardiomyopathy
  • arrhythmogenic right ventricular dysplasia
  • diagnosis
  • genetic testing
  • mutation
  • TASK-FORCE CRITERIA
  • DYSPLASIA/CARDIOMYOPATHY
  • PLAKOPHILIN-2
  • DESMOGLEIN-2
  • DIAGNOSIS
  • VARIANTS
  • DISEASE
  • IMPACT

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