Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3.

Kühnisch J1,2, Herbst C1,2,3, Al-Wakeel-Marquard N2,3,4, Dartsch J1, Holtgrewe M5,6, Baban A7, Mearini G8,9, Hardt J10,11, Kolokotronis K12, Gerull B13, Carrier L8,9, Beule D5,14, Schubert S2,3, Messroghli D2,15,16, Degener F2,3,4, Berger F2,3,17, Klaassen S1,2,17.

Author information

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: DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
3: Department of Congenital Heart Disease - Pediatric Cardiology, German Heart Center Berlin, Berlin, Germany.
4: 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.
5: Berlin Institute of Health (BIH), Core Unit Bioinformtics, Berlin, Germany.
6: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Core Facility Bioinformatik, Berlin, Germany.
7: Pediatric Cardiology and Cardiac Arrhythmia/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.
8: Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
9: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
10: 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.
11: Berlin Institute of Health (BIH), Clinical Research Unit (CRU) - Biostatistics, Berlin, Germany.
12: Institute of Human Genetics, Biocenter, Julius-Maximilians-University Würzburg, Würzburg, Germany.
13: Comprehensive Heart Failure Center (CHFC) and Department of Medicine I, University and University Hospital Würzburg, Würzburg, Germany.
14: Max Delbrück Center for Molecuar Medicine, Berlin, Germany.
15: Department of Internal Medicine - Cardiology, German Heart Center Berlin, Berlin, Germany.
16: Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
17: Department of Pediatric Cardiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 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 NGS approach of 89 genes. At least one pathogenic or likely 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/likely 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. This article is protected by copyright. All rights reserved.