Atlas of the clinical genetics of human dilated cardiomyopathy.

Atlas of the clinical genetics of human dilated cardiomyopathy. Haas, J., Frese, K. S, Peil, B., Kloos, W., Keller, A., Nietsch, R., Feng, Z., Müller, S., Kayvanpour, E., Vogel, B., Sedaghat-Hamedani, F., Lim, W., Zhao, X., Fradkin, D., Köhler, D., Fischer, S., Franke, J., Marquart, S., Barb, I., Li, D. T., Amr, A., Ehlermann, P., Mereles, D., Weis, T., Hassel, S., Kremer, A., King, V., Wirsz, E., Isnard, R., Komajda, M., Serio, A., Grasso, M., Syrris, P., Wicks, E., Plagnol, V., Lopes, L., Gadgaard, T., Eiskjær, H., Jørgensen, M., Garcia-Giustiniani, D., Ortiz-Genga, M., Crespo-Leiro, M. G, Deprez, R. H L. D., Christiaans, I., van Rijsingen, I. A, Wilde, A. A, Waldenstrom, A., Bolognesi, M., Bellazzi, R., Mörner, S., Bermejo, J. L., Monserrat, L., Villard, E., Mogensen, J., Pinto, Y. M, Charron, P., Elliott, P., Arbustini, E., Katus, H. A, & Meder, B. European heart journal, 36:1123–135a, May, 2015.
doi abstract bibtex

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. 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. 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.

@Article{Haas2015,
  author          = {Haas, Jan and Frese, Karen S and Peil, Barbara and Kloos, Wanda and Keller, Andreas and Nietsch, Rouven and Feng, Zhu and Müller, Sabine and Kayvanpour, Elham and Vogel, Britta and Sedaghat-Hamedani, Farbod and Lim, Wei-Keat and Zhao, Xiaohong and Fradkin, Dmitriy and Köhler, Doreen and Fischer, Simon and Franke, Jennifer and Marquart, Sabine and Barb, Ioana and Li, Daniel Tian and Amr, Ali and Ehlermann, Philipp and Mereles, Derliz and Weis, Tanja and Hassel, Sarah and Kremer, Andreas and King, Vanessa and Wirsz, Emil and Isnard, Richard and Komajda, Michel and Serio, Alessandra and Grasso, Maurizia and Syrris, Petros and Wicks, Eleanor and Plagnol, Vincent and Lopes, Luis and Gadgaard, Tenna and Eiskjær, Hans and Jørgensen, Mads and Garcia-Giustiniani, Diego and Ortiz-Genga, Martin and Crespo-Leiro, Maria G and Deprez, Rondal H Lekanne Dit and Christiaans, Imke and van Rijsingen, Ingrid A and Wilde, Arthur A and Waldenstrom, Anders and Bolognesi, Martino and Bellazzi, Riccardo and Mörner, Stellan and Bermejo, Justo Lorenzo and Monserrat, Lorenzo and Villard, Eric and Mogensen, Jens and Pinto, Yigal M and Charron, Philippe and Elliott, Perry and Arbustini, Eloisa and Katus, Hugo A and Meder, Benjamin},
  title           = {Atlas of the clinical genetics of human dilated cardiomyopathy.},
  journal         = {European heart journal},
  year            = {2015},
  volume          = {36},
  pages           = {1123--135a},
  month           = may,
  issn            = {1522-9645},
  abstract        = {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. 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. 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.},
  chemicals       = {Genetic Markers},
  citation-subset = {IM},
  completed       = {2016-02-01},
  country         = {England},
  doi             = {10.1093/eurheartj/ehu301},
  issn-linking    = {0195-668X},
  issue           = {18},
  keywords        = {Cardiomyopathy, Dilated, diagnosis, genetics; Europe; Feasibility Studies; Female; Genetic Markers, genetics; Genotype; Heterozygote; Humans; Male; Mutation, genetics; Phenotype; Residence Characteristics; Sequence Analysis, DNA, methods; Cardiomyopathy; Diagnosis; Genetics; Patients},
  nlm-id          = {8006263},
  owner           = {NLM},
  pii             = {ehu301},
  pmid            = {25163546},
  pubmodel        = {Print-Electronic},
  pubstatus       = {ppublish},
  revised         = {2015-05-08},
}

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