title: Atlas of the clinical genetics of human dilated cardiomyopathy.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Institute of Medical Biometry and Informatics (IMBI), University Hospital Heidelberg, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany.
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authors.affiliation: Department of Human Genetics, Saarland University, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany.
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authors.affiliation: Department of Human Genetics, Saarland University, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Siemens Corporate Technology, Princeton, USA.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany.
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authors.affiliation: Siemens AG, Österreich.
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authors.affiliation: INSERM UMRS-956, UPMC Univ Paris 6, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
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authors.affiliation: INSERM UMRS-956, UPMC Univ Paris 6, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
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authors.affiliation: Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
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authors.affiliation: Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
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authors.affiliation: Department of Cardiology, Aarhus University Hospital, Denmark.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany Klaus Tschira Institute for Computational Cardiology, University of Heidelberg, Germany.
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authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Germany Klaus Tschira Institute for Computational Cardiology, University of Heidelberg, Germany benjamin.meder@med.uni-heidelberg.de.
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mesh_terms: D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics*; D005060:Europe; D005240:Feasibility Studies; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012111:Residence Characteristics; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D005819:Genetic Markers
keywords: Cardiomyopathy; Diagnosis; Genetics; Patients