Atlas of the clinical genetics of human dilated cardiomyopathy

作者：Jan Haas, Karen Frese, Barbara Peil, Wanda Kloos, Andreas Keller, Rouven Nietsch, Zhu Feng, Sabine C. Müller, Elham Kayvanpour, Britta Vogel, Farbod Sedaghat‐Hamedani, Wei-Keat Lim, Xiaohong Zhao, Dmitriy Fradkin, Doreen Köhler, Simon Fischer, Jennifer Franke, Sabine Marquart, Ioana Barb, Daniel Tian Li, Ali Amr, Philipp Ehlermann, Derliz Mereles, Tanja Weis, Sarah Hassel, Andreas Kremer, Vanessa King, Emil Wirsz, Richard Isnard, Michel Komajda, Alessandra Serio, Maurizia Grasso, Petros Syrris, Eleanor C. Wicks, Vincent Plagnol, Luís Rocha Lopes, Tenna Gadgaard, Hans Eiskjær, Mads Emil Jørgensen, Diego A. García-Giustiniani, Martín Ortiz-Genga, María G. Crespo‐Leiro, Ronald H. Lekanne Deprez, Imke Christiaans, Ingrid A van Rijsingen, Arthur A. Wilde, Anders P. Waldenström, Martino Bolognesi, Riccardo Bellazzi, Stellan Mörner, Justo Lorenzo Bermejo, Lorenzo Monserrat, Eric Villard, Jens Mogensen, Yigal M. Pinto, Philippe Charron, Perry Mark Elliott, Eloisa Arbustini, Hugo Albert Katus, Benjamin Meder · 发表于：European Heart Journal · 年份：2014 · DOI：10.1093/eurheartj/ehu301 · 被引用次数：577 · 研究领域：Cardiomyopathy and Myosin Studies、Cardiac Fibrosis and Remodeling、Cardiac electrophysiology and arrhythmias

AIM: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. METHODS AND RESULTS: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected ge...