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University of Groningen Paediatric Cardiomyopathies Herkert, Johanna University of Groningen Paediatric cardiomyopathies Herkert, Johanna Cornelia DOI: 10.33612/diss.97534698 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Herkert, J. C. (2019). Paediatric cardiomyopathies: an evolving landscape of genetic aetiology and diagnostic applications. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.97534698 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 11-10-2021 Paediatric cardiomyopathies An evolving landscape of genetic aetiology and diagnostic applications Johanna C. Herkert ISBN (printed version): 978-94-034-1899-5 ISBN (electronic version): 978-94-034-1898-8 Cover design and layout: © evelienjagtman.com Printing: Ipskamp Printing, Enschede, the Netherlands Printing of this thesis was financially supported by the Graduate School of Medical Sciences, University Medical Center Groningen, the Netherlands © 2019, J.C. Herkert, the Netherlands All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior permission of the author or, when appropriate, of the publisher of the publications included in this thesis. Paediatric cardiomyopathies An evolving landscape of genetic aetiology and diagnostic applications Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 16 oktober 2019 om 11.00 uur door Johanna Cornelia Herkert geboren op 27 februari 1981 te Epe Promotores Prof. dr. I.M. van Langen Prof. dr. M.P. van den Berg Copromotor Dr. J.D.H. Jongbloed Beoordelingscommissie Prof. dr. M.M.A.M. Mannens Prof. dr. N.A. Blom Prof. dr. V.V.A.M. Knoers Paranimfen Mieke Kerstjens Cyrille Herkert Voor Maria, Marije, Jeffrey, Engbert, Yoni, Antine, Rianne, Sharona, Sophie, Dylan, Jade, Asya, Mart, Lauri, Eslem, Naomi, Kick, Sander, Tiger, Hendrik, Jeroen, Michiel, Mart, Marlies, Felicia, Emam, Kaiden, Twan, Stef, Ilse, Jarno, Matthijs, Eva, Oemaima, Sylvia, Abdulsamet, Peter, Rick, Jefta, Mart, Jette, Koen, Monica, Meike, Noelle, Rien, Colin, Christian, Dennis, Luca, Maik, Niek, Pascal, Roland, Janne en Amber Contents Part I Introduction Chapter 1 General Introduction & Aims and outline of this thesis 11 Chapter 2 Clinical utility gene card for: dilated cardiomyopathy (CMD) 39 Chapter 3 Compound heterozygous or homozygous truncating MYBPC3 57 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects Part II Yield and strategies for genetic testing and data analysis Chapter 4 Toward an effective exome-based genetic testing strategy in paediatric 81 dilated cardiomyopathy Chapter 5 Improving the diagnostic yield of exome-sequencing by predicting gene- 147 phenotype associations using large-scale gene expression analysis Part III Rare and novel genes Chapter 6 Novel SPEG mutations in congenital myopathies: genotype-phenotype 185 correlations Chapter 7 Biallelic truncating mutations in ALPK3 cause severe paediatric 201 cardiomyopathy Chapter 8 Expanding the clinical and genetic spectrum of ALPK3 variants: 229 phenotypes identified in paediatric cardiomyopathy patients and adults with heterozygous variants Chapter 9 Homozygous damaging SOD2 variant causes lethal neonatal dilated 287 cardiomyopathy Part IV Summary and general discussion Chapter 10 Summary 319 Chapter 11 Discussion and future perspectives 327 Appendix Nederlandse samenvatting 347 List of abbreviations 255 List of authors and affiliations 361 Curriculum vitae 373 List of publications 377 385 Dankwoord Part I Introduction Chapter 1 General Introduction Introduction General Introduction 1 Cardiomyopathies, which are characterized by abnormal ventricular myocardial structure or function, are the most common cause of childhood heart failure. They affect 1 to 2 individuals per 100,000 annually, with the highest incidence in children under age 1 year.1-4 The aetiology of paediatric cardiomyopathy is diverse and includes coronary artery abnormalities and infectious, environmental (e.g. toxins) and genetic causes. Originally, the Internal Society and Federation of Cardiology Task Forces and the World Health Organisation, made a differentiation between idiopathic or ‘primary’ heart muscle disorders and heart muscle disorders with similar morphological features but distinct aetiology, such as cardiomyopathy due to metabolic, neuromuscular, syndromic or inflammatory diseases.5 The genetic revolution of the past decades made the term ‘idiopathic’ largely redundant as the ‘idiopathic phenotypes’ were increasingly linked to specific genes and gene variants. However, in the clinical setting, classification of cardiomyopathies continues to be driven mainly by clinical presentation, morphological criteria and heart function.6 Classification of cardiomyopathies There are two major classification systems of cardiomyopathy currently being used: the classification system of the European Society of Cardiology (ESC)7 and the definition and classification system of American College of Cardiology/American Heart Association (AHA).8 The ESC classification is primarily based on phenotype and cardiac morphology. The AHA classification relies substantially on the aetiology of myocardial diseases and is based on advances made in the understanding of the genomic and molecular causes of cardiomyopathy. According to the ESC “cardiomyopathy” is defined as “a myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease, sufficient to cause the observed myocardial abnormality”.7 In this classification system, cardiomyopathies are sub-classified into five distinct groups: hypertrophic, dilated, restrictive, arrhythmogenic and “unclassified” cardiomyopathies including left ventricular noncompaction (or noncompaction cardiomyopathy, NCCM). Each phenotype can be divided into familial/genetic and non-familial/non-genetic forms. Familial/genetic cardiomyopathy includes sarcomeric, Z-band, cytoskeletal, nuclear membrane and intercalated disk protein defects; inborn errors of metabolism (IEM); syndromic cardiomyopathy; mitochondrial diseases and familial amyloidosis. Patients with identified de novo variants are allocated to the familial/genetic category as their disorder is caused by the genetic aberration and can be passed on to their offspring7 (Figure 1A). 13 Chapter 1 In the classification system proposed by the AHA, the definition of cardiomyopathy is somewhat different from that of the ESC: “Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic. Cardiomyopathies are either confined to the heart or are part of generalized systemic disorders, and often lead to cardiovascular death or progressive heart failure-related disability”.8 The AHA classification system divides the cardiomyopathies into two major groups: primary cardiomyopathies that are solely or predominantly confined to heart muscle, including genetic, mixed and acquired cardiomyopathies, and secondary cardiomyopathies, either genetic or non-genetic, that show myocardial involvement as part of a generalized systemic (multi-organ) disorder (Figure 1B). In this classification system, hypertrophic cardiomyopathy (HCM), left ventricular noncompaction and arrhythmogenic cardiomyopathy (ACM) are categorized as primary genetic cardiomyopathies. Dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) belong to the mixed primary subcategory. Mitochondrial disorders and Danon disease are considered primary (genetic) cardiomyopathies, while other (genetic) glycogen storage disorders, IEM, neuromuscular disorders and malformation syndromes are categorized as secondary cardiomyopathies (Figure 1B). While the AHA definition and classification of cardiomyopathy incorporates both mechanical and electrical diseases, the ESC rules out ion channel and conduction system diseases from the umbrella of cardiomyopathies. Both classification systems are aimed at classifying
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