期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 69, 期 17, 页码 2134-2145出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2017.02.046
关键词
cardiomyopathy; channelopathy; molecular autopsy; next-generation sequencing; unexplained sudden death
资金
- Cardiac Risk in the Young
- British Heart Foundation
- BHF Clinical Research Training Fellowship [FS/11/71/28918]
- NMRC Singapore
- Leducq Foundation
- MRC UK
- Tanoto Foundation
- SingHealth/Duke-NUS Precision Medicine Institute (PRISM)
- Cure Kids (New Zealand)
- NIHR Royal Brompton Cardiovascular Biomedical Research Unit
- Wellcome Trust
- Dutch Heart Foundation CVON-PREDICT project [CVON2012-10]
- Biotronik
- St. Jude Medical
- British Heart Foundation [FS/11/71/28918, SP/10/10/28431] Funding Source: researchfish
- Medical Research Council [MC_U120085815, MC_UP_1102/20] Funding Source: researchfish
- National Institute for Health Research [CL-2011-16-501] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0011573] Funding Source: researchfish
- Wellcome Trust [107469/Z/15/Z] Funding Source: researchfish
- MRC [MC_U120085815, MC_UP_1102/20] Funding Source: UKRI
BACKGROUND Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. OBJECTIVES This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. METHODS We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. RESULTS A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 x 10(-5)). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. CONCLUSIONS Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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