|
|||||
|
|
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3 |
|
| Authors: | Jirko Kühnisch Christopher Herbst Nadya Al-Wakeel-Marquard Josephine Dartsch Manuel Holtgrewe Anwar Baban Giulia Mearini Juliane Hardt Konstantinos Kolokotronis Brenda Gerull Lucie Carrier Dieter Beule Stephan Schubert Daniel Messroghli Franziska Degener Felix Berger Sabine Klaassen |
| Affiliation: | 1. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany;2. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany DZHK (German Centre for Cardiovascular Research), Berlin, Germany Department of Congenital Heart Disease - Pediatric Cardiology, German Heart Center Berlin, Berlin, Germany;3. DZHK (German Centre for Cardiovascular Research), Berlin, Germany Department of Congenital Heart Disease - Pediatric Cardiology, German Heart Center Berlin, Berlin, Germany Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Berlin, Germany;4. Core Unit Bioinformtics, Berlin Institute of Health (BIH), Berlin, Germany;5. Pediatric Cardiology and Cardiac Arrhythmia/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy;6. Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Hamburg, Germany;7. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Biometry and Clinical Epidemiology (iBikE), Berlin, Germany Clinical Research Unit (CRU) – Biostatistics, Berlin Institute of Health (BIH), Berlin, Germany;8. Institute of Human Genetics, Biocenter, Julius-Maximilians-University Würzburg, Würzburg, Germany;9. Comprehensive Heart Failure Center (CHFC) and Department of Medicine I, University and University Hospital Würzburg, Würzburg, Germany;10. Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;11. DZHK (German Centre for Cardiovascular Research), Berlin, Germany Department of Congenital Heart Disease - Pediatric Cardiology, German Heart Center Berlin, Berlin, Germany;12. DZHK (German Centre for Cardiovascular Research), Berlin, Germany |
| Abstract: | The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel-based next-generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP. |
| Keywords: | cardiomyopathy genetics pediatrics sarcomere TNNI3 |