Stefan Rupp1, Moataz Felimban2, Anne Schänzer3, Dietmar Schranz2, Christoph Marschall4, Martin Zenker5, Thushiha Logeswaran2, Christoph Neuhäuser2, Josef Thul2, Christian Jux2, Andreas Hahn6. 1. Pediatric Heart Center, Justus-Liebig University, Feulgenstrasse 12, 35385, Giessen, Germany. Stefan.rupp@paediat.med.uni-giessen.de. 2. Pediatric Heart Center, Justus-Liebig University, Feulgenstrasse 12, 35385, Giessen, Germany. 3. Institute of Neuropathology, Justus-Liebig University, Giessen, Germany. 4. Center of Human Genetics and Laboratory Diagnostics, Martinsried, Germany. 5. Institute of Human Genetics, University Hospital, Otto-von-Guericke-University, Magdeburg, Germany. 6. Department of Child Neurology, Justus-Liebig University, Giessen, Germany.
Abstract
BACKGROUND: Previous investigations assessing the genetic cause of pediatric hypertrophic cardiomyopathy (HCM) found underlying genetic mutations in 50-60% of cases. The purpose of our study was to analyze whether this number can be augmented by applying next-generation sequencing and directing further diagnostics by discussing unsolved cases in a multidisciplinary board. METHODS AND RESULTS: 42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich's ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%). CONCLUSION: A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.
BACKGROUND: Previous investigations assessing the genetic cause of pediatric hypertrophic cardiomyopathy (HCM) found underlying genetic mutations in 50-60% of cases. The purpose of our study was to analyze whether this number can be augmented by applying next-generation sequencing and directing further diagnostics by discussing unsolved cases in a multidisciplinary board. METHODS AND RESULTS: 42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich's ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%). CONCLUSION: A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.
Authors: Julia Schuld; Peter F M van der Ven; Anne Schänzer; Elisabeth Schumann; Diana Zengeler; Lisann Gulatz; Giovanni Maroli; Uwe Ahting; Anke Sprengel; Sabine Gräf; Andreas Hahn; Christian Jux; Till Acker; Dieter O Fürst; Stefan Rupp Journal: J Muscle Res Cell Motil Date: 2021-03-12 Impact factor: 2.698
Authors: Martin Zschirnt; Josef Thul; Hakan Akintürk; Klaus Valeske; Dietmar Schranz; Susanne Skrzypek; Matthias Müller; Christian Jux; Andreas Hahn; Stefan Rupp Journal: J Pers Med Date: 2020-11-27
Authors: Grigorios Chatzantonis; Michael Bietenbeck; Anca Florian; Claudia Meier; Philipp Stalling; Dennis Korthals; Holger Reinecke; Ali Yilmaz Journal: Clin Res Cardiol Date: 2020-05-05 Impact factor: 5.460