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Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy

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.IntroductionLeft ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, t...

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Main Authors: Sedaghat-Hamedani, Farbod (Author) , Haas, Jan (Author) , Feng, Zhu (Author) , Kayvanpour, Elham (Author) , Lai, Chung Lun Alan (Author) , Frese, Karen S. (Author) , Pribe-Wolferts, Regina (Author) , Amr, Ali (Author) , Li, Daniel Tian (Author) , Shirvani-Samani, Omid (Author) , Carstensen, Avisha (Author) , Martins Bordalo, Diana (Author) , Müller, Marion (Author) , Fischer, Christine (Author) , Ehlermann, Philipp (Author) , Dieterich, Christoph (Author) , Katus, Hugo (Author) , Meder, Benjamin (Author)
Format: Article (Journal)
Language:English
Published: 06 October 2017
In: European heart journal
Year: 2017, Volume: 38, Issue: 46, Pages: 3449-3460
ISSN:1522-9645
DOI:10.1093/eurheartj/ehx545
Online Access:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1093/eurheartj/ehx545
Verlag, kostenfrei, Volltext: https://academic.oup.com/eurheartj/article/38/46/3449/4364851
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Author Notes:Farbod Sedaghat-Hamedani, Jan Haas, Feng Zhu, Christian Geier, Elham Kayvanpour, Martin Liss, Alan Lai, Karen Frese, Regina Pribe-Wolferts, Ali Amr, Daniel Tian Li, Omid Shirvani Samani, Avisha Carstensen, Diana Martins Bordalo, Marion Müller, Christine Fischer, Jing Shao, Jing Wang, Ming Nie, Li Yuan, Sabine Haßfeld, Christine Schwartz, Min Zhou, Zihua Zhou, Yanwen Shu, Min Wang, Kai Huang, Qiutang Zeng, Longxian Cheng, Tobias Fehlmann, Philipp Ehlermann, Andreas Keller, Christoph Dieterich, Katrin Streckfuß-Bömeke, Yuhua Liao, Michael Gotthardt, Hugo A. Katus, Benjamin Meder
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Summary: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.IntroductionLeft 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 resultsIn 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.ConclusionOur 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.
Item Description:Gesehen am 11.12.2017
Physical Description:Online Resource
ISSN:1522-9645
DOI:10.1093/eurheartj/ehx545

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