Farbod Sedaghat-Hamedani1,2, Jan Haas1,2, Feng Zhu1,3, Christian Geier4,5, Elham Kayvanpour1,2, Martin Liss5,6, Alan Lai1,2, Karen Frese1,2, Regina Pribe-Wolferts1, Ali Amr1,2, Daniel Tian Li1,2, Omid Shirvani Samani1,2, Avisha Carstensen1, Diana Martins Bordalo1,2, Marion Müller1,2, Christine Fischer7, Jing Shao3, Jing Wang8, Ming Nie3, Li Yuan9, Sabine Haßfeld10, Christine Schwartz4, Min Zhou11, Zihua Zhou3, Yanwen Shu3, Min Wang3, Kai Huang3, Qiutang Zeng3, Longxian Cheng3, Tobias Fehlmann12, Philipp Ehlermann1, Andreas Keller12, Christoph Dieterich2,13, Katrin Streckfuß-Bömeke14,15, Yuhua Liao3, Michael Gotthardt5,6, Hugo A Katus1,2, Benjamin Meder1,2. 1. Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. 2. DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany. 3. Department of Cardiology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China. 4. Experimental and Clinical Research Center (ECRC), A Joint Cooperation of Charité Medical Faculty and Max Delbrück Center for Molecular Medicine (MDC), Augustenburger Platz 1, 13353 Berlin, Germany. 5. DZHK (German Centre for Cardiovascular Research), Berlin, Germany. 6. Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany. 7. Department of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. 8. Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China. 9. Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China. 10. Department of Cardiology, Virchow Klinikum, Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. 11. Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 12. Department of Bioinformatics, University of Saarland, Building E2.1, 66123 Saarbrücken, Germany. 13. Department of Medicine III, Klaus Tschira Institute for Computational Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. 14. Department of Cardiology and Pneumology, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. 15. DZHK (German Centre for Cardiovascular Research), Göttingen, Germany.
Abstract
AIMS: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. INTRODUCTION: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. METHODS AND RESULTS: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. CONCLUSION: Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. INTRODUCTION: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. METHODS AND RESULTS: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. CONCLUSION: Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome. Published on behalf of the European Society of Cardiology. All rights reserved.
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