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 journalArticle

Abstract

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
Volume36
Issue number18
DOIs
Publication statusPublished - May 7 2015

Fingerprint

Atlases
Medical Genetics
Dilated Cardiomyopathy
Genes
Plakophilins
Desmoplakins
Mutation
Desmoglein 2
Desmocollins
Channelopathies
Connectin
Genetic Databases
Ryanodine Receptor Calcium Release Channel
Hypertrophic Cardiomyopathy
Mutation Rate
Cardiomyopathies
Phenotype

Keywords

  • Cardiomyopathy
  • Diagnosis
  • Genetics
  • Patients

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Haas, J., Frese, K. S., Peil, B., Kloos, W., Keller, A., Nietsch, R., ... Meder, B. (2015). Atlas of the clinical genetics of human dilated cardiomyopathy. European Heart Journal, 36(18), 1123-1135. https://doi.org/10.1093/eurheartj/ehu301

Atlas of the clinical genetics of human dilated cardiomyopathy. / Haas, Jan; Frese, Karen S.; Peil, Barbara; Kloos, Wanda; Keller, Andreas; Nietsch, Rouven; Feng, Zhu; Müller, Sabine; Kayvanpour, Elham; Vogel, Britta; Sedaghat-Hamedani, Farbod; Lim, Wei Keat; Zhao, Xiaohong; Fradkin, Dmitriy; Köhler, Doreen; Fischer, Simon; Franke, Jennifer; Marquart, Sabine; Barb, Ioana; Li, Daniel Tian; Amr, Ali; Ehlermann, Philipp; Mereles, Derliz; Weis, Tanja; Hassel, Sarah; Kremer, Andreas; King, Vanessa; Wirsz, Emil; Isnard, Richard; Komajda, Michel; Serio, Alessandra; Grasso, Maurizia; Syrris, Petros; Wicks, Eleanor; Plagnol, Vincent; Lopes, Luis; Gadgaard, Tenna; Eiskjær, Hans; Jørgensen, Mads; Garcia-Giustiniani, Diego; Ortiz-Genga, Martin; Crespo-Leiro, Maria G.; Deprez, Rondal H Lekanne Dit; Christiaans, Imke; Van Rijsingen, Ingrid A.; Wilde, Arthur A.; Waldenstrom, Anders; Bolognesi, Martino; Bellazzi, Riccardo; Mörner, Stellan; Bermejo, Justo Lorenzo; Monserrat, Lorenzo; Villard, Eric; Mogensen, Jens; Pinto, Yigal M.; Charron, Philippe; Elliott, Perry; Arbustini, Eloisa; Katus, Hugo A.; Meder, Benjamin.

In: European Heart Journal, Vol. 36, No. 18, 07.05.2015, p. 1123-1135.

Research output: Contribution to journalArticle

Haas, J, Frese, KS, Peil, B, Kloos, W, Keller, A, Nietsch, R, Feng, Z, Müller, S, Kayvanpour, E, Vogel, B, Sedaghat-Hamedani, F, Lim, WK, Zhao, X, Fradkin, D, Köhler, D, Fischer, S, Franke, J, Marquart, S, Barb, I, Li, DT, 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, MG, Deprez, RHLD, Christiaans, I, Van Rijsingen, IA, Wilde, AA, Waldenstrom, A, Bolognesi, M, Bellazzi, R, Mörner, S, Bermejo, JL, Monserrat, L, Villard, E, Mogensen, J, Pinto, YM, Charron, P, Elliott, P, Arbustini, E, Katus, HA & Meder, B 2015, 'Atlas of the clinical genetics of human dilated cardiomyopathy', European Heart Journal, vol. 36, no. 18, pp. 1123-1135. https://doi.org/10.1093/eurheartj/ehu301
Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R et al. Atlas of the clinical genetics of human dilated cardiomyopathy. European Heart Journal. 2015 May 7;36(18):1123-1135. https://doi.org/10.1093/eurheartj/ehu301
Haas, Jan ; Frese, Karen S. ; Peil, Barbara ; Kloos, Wanda ; Keller, Andreas ; Nietsch, Rouven ; Feng, Zhu ; Müller, Sabine ; Kayvanpour, Elham ; Vogel, Britta ; Sedaghat-Hamedani, Farbod ; Lim, Wei Keat ; Zhao, Xiaohong ; Fradkin, Dmitriy ; Köhler, Doreen ; Fischer, Simon ; Franke, Jennifer ; Marquart, Sabine ; Barb, Ioana ; Li, Daniel Tian ; Amr, Ali ; Ehlermann, Philipp ; Mereles, Derliz ; Weis, Tanja ; Hassel, Sarah ; Kremer, Andreas ; King, Vanessa ; Wirsz, Emil ; Isnard, Richard ; Komajda, Michel ; Serio, Alessandra ; Grasso, Maurizia ; Syrris, Petros ; Wicks, Eleanor ; Plagnol, Vincent ; Lopes, Luis ; Gadgaard, Tenna ; Eiskjær, Hans ; Jørgensen, Mads ; Garcia-Giustiniani, Diego ; Ortiz-Genga, Martin ; Crespo-Leiro, Maria G. ; Deprez, Rondal H Lekanne Dit ; Christiaans, Imke ; Van Rijsingen, Ingrid A. ; Wilde, Arthur A. ; Waldenstrom, Anders ; Bolognesi, Martino ; Bellazzi, Riccardo ; Mörner, Stellan ; Bermejo, Justo Lorenzo ; Monserrat, Lorenzo ; Villard, Eric ; Mogensen, Jens ; Pinto, Yigal M. ; Charron, Philippe ; Elliott, Perry ; Arbustini, Eloisa ; Katus, Hugo A. ; Meder, Benjamin. / Atlas of the clinical genetics of human dilated cardiomyopathy. In: European Heart Journal. 2015 ; Vol. 36, No. 18. pp. 1123-1135.
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abstract = "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.",
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TY - JOUR

T1 - Atlas of the clinical genetics of human dilated cardiomyopathy

AU - Haas, Jan

AU - Frese, Karen S.

AU - Peil, Barbara

AU - Kloos, Wanda

AU - Keller, Andreas

AU - Nietsch, Rouven

AU - Feng, Zhu

AU - Müller, Sabine

AU - Kayvanpour, Elham

AU - Vogel, Britta

AU - Sedaghat-Hamedani, Farbod

AU - Lim, Wei Keat

AU - Zhao, Xiaohong

AU - Fradkin, Dmitriy

AU - Köhler, Doreen

AU - Fischer, Simon

AU - Franke, Jennifer

AU - Marquart, Sabine

AU - Barb, Ioana

AU - Li, Daniel Tian

AU - Amr, Ali

AU - Ehlermann, Philipp

AU - Mereles, Derliz

AU - Weis, Tanja

AU - Hassel, Sarah

AU - Kremer, Andreas

AU - King, Vanessa

AU - Wirsz, Emil

AU - Isnard, Richard

AU - Komajda, Michel

AU - Serio, Alessandra

AU - Grasso, Maurizia

AU - Syrris, Petros

AU - Wicks, Eleanor

AU - Plagnol, Vincent

AU - Lopes, Luis

AU - Gadgaard, Tenna

AU - Eiskjær, Hans

AU - Jørgensen, Mads

AU - Garcia-Giustiniani, Diego

AU - Ortiz-Genga, Martin

AU - Crespo-Leiro, Maria G.

AU - Deprez, Rondal H Lekanne Dit

AU - Christiaans, Imke

AU - Van Rijsingen, Ingrid A.

AU - Wilde, Arthur A.

AU - Waldenstrom, Anders

AU - Bolognesi, Martino

AU - Bellazzi, Riccardo

AU - Mörner, Stellan

AU - Bermejo, Justo Lorenzo

AU - Monserrat, Lorenzo

AU - Villard, Eric

AU - Mogensen, Jens

AU - Pinto, Yigal M.

AU - Charron, Philippe

AU - Elliott, Perry

AU - Arbustini, Eloisa

AU - Katus, Hugo A.

AU - Meder, Benjamin

PY - 2015/5/7

Y1 - 2015/5/7

N2 - 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.

AB - 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.

KW - Cardiomyopathy

KW - Diagnosis

KW - Genetics

KW - Patients

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