Atlas of the clinical genetics of human dilated cardiomyopathy

Jan Haas, Karen S. Frese, Barbara Peil, Wanda Kloos, Andreas Keller, Rouven Nietsch, Zhu Feng, Sabine 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 LiAli 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 Wicks, Vincent Plagnol, Luis Lopes, Tenna Gadgaard, Hans Eiskjær, Mads Jørgensen, Diego Garcia-Giustiniani, Martin Ortiz-Genga, Maria G. Crespo-Leiro, Rondal H Lekanne Dit Deprez, Imke Christiaans, Ingrid A. Van Rijsingen, Arthur A. Wilde, Anders Waldenstrom, Martino Bolognesi, Riccardo Bellazzi, Stellan Mörner, Justo Lorenzo Bermejo, Lorenzo Monserrat, Eric Villard, Jens Mogensen, Yigal M. Pinto, Philippe Charron, Perry Elliott, Eloisa Arbustini, Hugo A. Katus, Benjamin Meder

Research output: Contribution to journalArticlepeer-review


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 genes. Conclusion This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.

Original languageEnglish
Pages (from-to)1123-1135
Number of pages13
JournalEuropean Heart Journal
Issue number18
Publication statusPublished - May 7 2015


  • Cardiomyopathy
  • Diagnosis
  • Genetics
  • Patients

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)


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