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Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy

Item Type:Article
Title:Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy
Creators Name:Sedaghat-Hamedani, F. and Haas, J. and Zhu, F. and Geier, C. and Kayvanpour, E. and Liss, M. and Lai, A. and Frese, K. and Pribe-Wolferts, R. and Amr, A. and Li, D.T. and Samani, O.S. and Carstensen, A. and Bordalo, D.M. and Müller, M. and Fischer, C. and Shao, J. and Wang, J. and Nie, M. and Yuan, L. and Haßfeld, S. and Schwartz, C. and Zhou, M. and Zhou, Z. and Shu, Y. and Wang, M. and Huang, K. and Zeng, Q. and Cheng, L. and Fehlmann, T. and Ehlermann, P. and Keller, A. and Dieterich, C. and Streckfuß-Bömeke, K. and Liao, Y. and Gotthardt, M. and Katus, H.A. and Meder, B.
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.
Keywords:RBM20, Non-Compaction Cardiomyopathy, Titin, Next-Generation Whole-Exome Sequencing
Source:European Heart Journal
Publisher:Oxford University Press
Page Range:3449-3460
Date:7 December 2017
Official Publication:https://doi.org/10.1093/eurheartj/ehx545
PubMed:View item in PubMed

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