© 2011 by the American College of Cardiology Foundation
CLINICAL RESEARCH: HEART RHYTHM DISORDER
Distinguishing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia–Associated Mutations From Background Genetic Noise
Jamie D. Kapplinger, BA*, Andrew P. Landstrom, BS*, Benjamin A. Salisbury, PhD, Thomas E. Callis, PhD, Guido D. Pollevick, PhD, David J. Tester, BS*, Moniek G.P.J. Cox, MD,||, Zahir Bhuiyan, MD, PhD¶, Hennie Bikker, PhD¶, Ans C.P. Wiesfeld, MD, PhD**, Richard N.W. Hauer, MD,||, J. Peter van Tintelen, MD, PhD, Jan D.H. Jongbloed, PhD, Hugh Calkins, MD, Daniel P. Judge, MD, Arthur A.M. Wilde, MD, PhD,# and Michael J. Ackerman, MD, PhD*,,*
* Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
Departments of Medicine and Pediatrics/Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
Transgenomic Inc., New Haven, Connecticut
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
|| Interuniversity Cardiological Institute of The Netherlands, Utrecht, the Netherlands
¶ Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands
# Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands
** Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Department of Medical Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Manuscript received September 13, 2010; revised manuscript received November 18, 2010, accepted December 1, 2010.
* Reprint requests and correspondence: Dr. Michael J. Ackerman, Mayo Clinic, Windland Smith Rice Sudden Death Genomics Laboratory, Guggenheim 501, Rochester, Minnesota 55905 (Email: ackerman.michael@mayo.edu).
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.
Distinguishing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia-Associated Mutations From Background Genetic Noise -- Kapplinger et al. 57 (23): 2317 -- Journal of the American College of Cardiology
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