Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy.
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Sedaghat-Hamedani Farbod, Haas Jan, Zhu Feng, Geier Christian, Kayvanpour Elham, Liss Martin, Lai Alan, Frese Karen, Pribe-Wolferts Regina, Amr Ali, Li Daniel Tian, Samani Omid Shirvani, Carstensen Avisha, Bordalo Diana Martins, Müller Marion, Fischer Christine, Shao Jing, Wang Jing, Nie Ming, Yuan Li, Haßfeld Sabine, Schwartz Christine, Zhou Min, Zhou Zihua, Shu Yanwen, Wang Min, Huang Kai, Zeng Qiutang, Cheng Longxian, Fehlmann Tobias, Ehlermann Philipp, Keller Andreas, Dieterich Christoph, Streckfuß-Bömeke Katrin, Liao Yuhua, Gotthardt Michael, Katus Hugo A, Meder Benjamin
Аннотация
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.