Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.

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2011-06

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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.

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10.1016/j.jacc.2010.12.036

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Kapplinger, JD, AP Landstrom, BA Salisbury, TE Callis, GD Pollevick, DJ Tester, MGPJ Cox, Z Bhuiyan, et al. (2011). Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. Journal of the American College of Cardiology, 57(23). pp. 2317–2327. 10.1016/j.jacc.2010.12.036 Retrieved from https://hdl.handle.net/10161/20329.

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Landstrom

Andrew Paul Landstrom

Associate Professor of Pediatrics

Dr. Landstrom is a physician scientist who specializes in the care of children and young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained death syndromes. As a clinician, he is trained in pediatric cardiology with a focus on arrhythmias and genetic diseases of the heart.  He specializes in caring for patients with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome.  He also specializes in the evaluation of children following a cardiac arrest or after the sudden and unexplained death of a family member.  He has expertise in cardiovascular genetics and uses it to identify individuals in a family who may be at risk of a disease, even if all clinical testing is negative.  As a scientist, he is trained in genetics and cell biology.  He runs a research lab exploring the genetic and molecular causes of arrhythmias, sudden unexplained death syndromes, and heart muscle disease (cardiomyopathies).  He utilizes patient-derived induced pluripotent stem cells and genetic mouse models to identify the mechanisms of cardiovascular genetic disease with the goal of developing novel therapies.


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