TY - JOUR
T1 - Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia- associated mutations from background genetic noise
AU - Kapplinger, Jamie D.
AU - Landstrom, Andrew P.
AU - Salisbury, Benjamin A.
AU - Callis, Thomas E.
AU - Pollevick, Guido D.
AU - Tester, David J.
AU - Cox, Moniek G.P.J.
AU - Bhuiyan, Zahir
AU - Bikker, Hennie
AU - Wiesfeld, Ans C.P.
AU - Hauer, Richard N.W.
AU - Van Tintelen, J. Peter
AU - Jongbloed, Jan D.H.
AU - Calkins, Hugh
AU - Judge, Daniel P.
AU - Wilde, Arthur A.M.
AU - Ackerman, Michael J.
N1 - Funding Information:
Mr. Kapplinger has stock interest in Clinical Data, Inc. Drs. Salisbury, Callis, and Pollevick are employees of Transgenomic Inc. Dr. Salisbury is also an employee and stock owner of Clinical Data, Inc. Mr. Tester receives modest royalties from Transgenomic Inc. Dr. Calkins directs a program that receives funding from Medtronic, Inc., St. Jude Medical, Inc., and Boston Scientific Corporation. Dr. Wilde serves on Transgenomic Inc.'s Scientific Advisory Board. Dr. Ackerman is a consultant for Transgenomic and chairs their FAMILION Medical/Scientific Advisory Board (approved by Mayo Clinic's Medical-Industry Relations Office and Conflict of Interest Review Board). In addition, “cardiac channel gene screen” and “know-how relating to long QT genetic testing” license agreements, resulting in consideration and royalty payments, were established between Genaissance Pharmaceuticals (then PGxHealth, and now Transgenomic) and Mayo Medical Ventures (now Mayo Clinic Health Solutions) in 2004. Dr. Ackerman is also a consultant for Biotronik, Boston Scientific Corporation, Medtronic, and St. Jude Medical. However, none of these entities provided financial support for this study. All other authors have reported that they have no relationships to disclose. The first 2 authors contributed equally to this work.
PY - 2011/6/7
Y1 - 2011/6/7
N2 - 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.
AB - 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.
KW - arrhythmogenic right ventricular cardiomyopathy
KW - arrhythmogenic right ventricular dysplasia
KW - diagnosis
KW - genetic testing
KW - mutation
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U2 - 10.1016/j.jacc.2010.12.036
DO - 10.1016/j.jacc.2010.12.036
M3 - Article
C2 - 21636032
AN - SCOPUS:79957975773
SN - 0735-1097
VL - 57
SP - 2317
EP - 2327
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 23
ER -