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Clinical Cardiogenetics PDF

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H.F. Baars P.A.F.M. Doevendans Arjan C. Houweling J. Peter van Tintelen Editors Clinical Cardiogenetics Second Edition 123 Clinical Cardiogenetics Hubert F. Baars (cid:129) Pieter A. F. M. Doevendans Arjan C. Houweling (cid:129) J. Peter van Tintelen Editors Clinical Cardiogenetics Second Edition Editors Hubert F. Baars Arjan C. Houweling Department of Cardiology Department of Clinical Genetics St. Elisabeth-TweeSteden Ziekenhuis VU University Medical Center Tilburg Amsterdam The Netherlands The Netherlands Pieter A. F. M. Doevendans J. Peter van Tintelen Department of Cardiology Department of Clinical Genetics University Medical Center Utrecht Academic Medical Center Utrecht Amsterdam The Netherlands The Netherlands ISBN 978-3-319-44202-0 ISBN 978-3-319-44203-7 (eBook) DOI 10.1007/978-3-319-44203-7 Library of Congress Control Number: 2016959797 © Springer International Publishing Switzerland 2016 T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Pref ace Dear colleague, Five years have passed since the release of the fi rst edition of Clinical Cardiogenetics. In the highly dynamic fi eld of cardiogenetics, revolutionary changes occur almost on a day-to-day basis. Therefore, a second edition has been long overdue. With contributions from worldwide leading experts in their fi elds, we feel this textbook will provide an up-to-date and useful refer- ence for those interested in the fi eld of cardiogenetics. Since the fi rst edition, the fi eld has changed dramatically by advances in technological possibilities such as the wide availability of next-generation sequencing allowing for sensitive and rapid analysis of a large number of disease-associated genes simultaneously. In addition, powerful new tools, such as the CRISPR- Cas9 system allowing rapid gene editing, have led to a revolution in understanding the molecu- lar basis of genetic disorders. Increasingly, the outcome of genetic testing infl uences management and follow-up of patients with hereditary disorders, for example, in screening for intracranial aneurysms in a patient with an A CTA2 or TGFBR1 mutation. Another example of the advances in the fi eld is provided by the exciting study by Green et al. who show that inhibi- tion of sarcomere contractile function by a small molecule in transgenic mice supressed the development of ventricular hypertrophy, cardiomyocyte disarray and myocardial fi brosis and attenuated hypertrophic and profi brotic gene expression.1 Their study indicates that, in the near future, alteration of the progression of HCM, a disease estimated to affect 1 in 500 people worldwide, may be feasible, whereas contemporary pharmacological treatment only provides symptom relief. The emergence of these novel techniques also poses questions in the fi elds of medical ethics, community genetics, and challenges in the interpretation of the ever increasing amount of variants of unknown clinical signifi cance found by genetic screening in index patients and their relatives. We expect the second edition will provide the reader the means to cope with these challenges in their day-to-day work. Tilburg , The Netherlands H. F. Baars Utrecht , The Netherlands P. A. F. Doevendans Amsterdam , The Netherlands A. C. Houweling Amsterdam , The Netherlands J. P. van Tintelen 1 E.M. Green et al. Science 351(6273):617–21, 2016. v Contents Part I Genetics 1 Introduction to Molecular Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Jan D.H. Jongbloed , Ronald H. Lekanne Deprez , and Matteo Vatta 2 Clinical Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 J. J. van der Smagt and Jodie Ingles Part II Cardiomyopathies 3 Introduction Hereditary Cardiomyopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Paul A. van der Zwaag and Maarten P. van den Berg 4 Hypertrophic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Imke Christiaans and Perry M. Elliott 5 Dilated Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 J.A. Jansweijer , R. Hershberger , and K.Y. Van Spaendonck 6 Arrhythmogenic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Moniek G. P. J. Cox , Ardan M. Saguner , Anneline S. te Riele , J. Peter van Tintelen , Firat Duru , Corinna Brunckhorst , and Richard N. W. Hauer 7 Left Ventricular Noncompaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Yvonne M. Hoedemaekers and Sabine Klaassen 8 Restrictive Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 J. H. Kirkels and N. de Jonge 9 Mitochondrial Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 N. de Jonge and J. H . Kirkels Part III Hereditary Arrhythmia Syndromes 10 Long QT Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Yanushi D. Wijeyeratne and Elijah R. Behr 11 Brugada Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Oscar Campuzano , Georgia Sarquella-Brugada , Ramon Brugada , and Josep Brugada 12 Catecholaminergic Polymorphic Ventricular Tachycardia . . . . . . . . . . . . . . . . . . 193 Krystien V. Lieve , Antoine Leenhardt , and Christian van der Werf 13 Short QT Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Christian Wolpert and Norman Rüb vii viii Contents 14 Idiopathic Ventricular Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 Masayasu Hiraoka and Tetsuo Sasano 15 A Molecular Genetic Perspective on Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . 227 Jason D. Roberts and Michael H. Gollob 16 Hereditary Cardiac Conduction Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Rafi k Tadros and Julia C adrin-Tourigny Part IV Hereditary Aortic Diseases 17 Heritable Thoracic Aortic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Barbara J.M. Mulder , Ingrid M.B.H. van de Laar , and Julie De Backer 18 Bicuspid Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 Aline Verstraeten , Jolien Roos-Hesselink , and Bart Loeys Part V Sudden Cardiac Death in the Young 19 Sudden Cardiac Death in the Young; Epidemiology and Cardiogenetic Evaluation of Victims and Their Relatives . . . . . . . . . . . . . . . . . . 311 Anneke Hendrix , Michiel L. Bots , and Arend Mosterd Part VI Miscellaneous 20 The Genetics of Mitral Valve Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Toon Oomen and J. Peter van Tintelen 21 Genetic Disorders of Lipoprotein Metabolism: Diagnosis and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 A. J. Cupido , R. M. Stoekenbroek , and J. J. P. Kastelein 22 Genetics of (Premature) Coronary Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . 355 Jeanette Erdmann and Heribert Schunkert 23 Hereditary Neuromuscular Diseases and Cardiac Involvement . . . . . . . . . . . . . 373 A.J. van der Kooi , K. Wahbi , G. Bonne , and M. de Visser 24 Future of Cardiogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 Martina C. Cornel , Isa Houwink , and Christopher Semsarian Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 Part I Genetics Introduction to Molecular Genetics 1 Jan D.H. Jongbloed , Ronald H. Lekanne Deprez , and Matteo Vatta Abstract In the last decades, molecular genetics has been rapidly integrated into the diagnostics of cardiovascular diseases. At fi rst to solve well-defi ned familial cases, but with the recent devel- opments of Next Generation Sequencing (NGS) also to identify genetic components involved in complex genetic cardiac diseases and to implement personalized genomics into routine patient care. In this introductory chapter several aspects of molecular genetics will be described and discussed. Firstly, the molecular basics of DNA, RNA and proteins and the different types of genetic mutations and their effects at the level of these different molecules will be addressed in the sections “DNA, RNA and proteins” and “Genetic Mutations”. As the mode of inheri- tance of mutations as well as the specifi c outcomes in mutation carriers may differ, several aspects related to this is being discussed in the “Genes in families and populations” section. Although NGS is becoming the most widely used technique to identify mutations, still several other techniques are being applied and in the “Molecular Genetic Techniques” section an overview of all currently used methods is provided. With the use of the aforementioned tech- niques often large amounts of data are being produced and careful analysis and interpretation of these data to dissect ‘noise’ from truly relevant information is of utmost importance. The section “Analysis and Interpretation” will focus on this. The use of molecular genetics already led to the identifi cation of signifi cant numbers of genes underlying cardiovascular diseases, however still more are to be discovered and approaches to do this are being described in the “Finding New disease genes” section. Finally, in the section “Clinical Genetic Diagnostics” the integration of molecular genetics in daily clinical genetic patient care is being addressed. Introduction I n recent years, comprehensive developments in genetics vastly improved our knowledge of inherited human diseases, J. D.H. Jongbloed (*) including genetic cardiac disorders. While previously only Department of Genetics , University of Groningen, University Medical Center Groningen , one to several candidate genes could be studied to search for Groningen , The Netherlands putative disease-causing mutations, currently whole exome R. H. Lekanne Deprez sequencing (WES) and whole genome sequencing (WGS) Department of Clinical Genetics, Academic Medical Center , enable the analysis of all variants within a personal genome, University of Amsterdam , Amsterdam , The Netherlands including those predisposing to disease. Important in this M. Vatta respect is the fact that the sequencing of a full genome can Department of Medical and Molecular Genetics, now be performed in reasonable time and at a relatively low and Krannert Institute of Cardiology and the Division of Cardiology, cost, as the $1000 genome is nowadays within reach. Department of Medicine , Indiana University School of Medicine , Indianapolis , IN , USA Moreover, this and other genotyping techniques provide the © Springer International Publishing Switzerland 2016 3 H.F. Baars et al. (eds.), Clinical Cardiogenetics, DOI 10.1007/978-3-319-44203-7_1 4 J.D.H. Jongbloed et al. possibility to identify variants, modifi ers, which have an DNA, RNA and Proteins effect on disease development by either leading to more severe symptoms or protecting carriers of pathogenic All information necessary to “build” a human is secured m utations from getting seriously ill. Interestingly, these within genomic and mitochondrial DNA (deoxyribonucleic developments also confronted the clinical genetics commu- acid) and the variation on that theme therefore too. The nity with the challenges of handling “big data” and building simple concept, however, of parts of the DNA (the genes) bioinformatical tools and methods to extract the truly being transcribed into RNA molecules that provide the pre- r elevant ones from the wealth of variants identifi ed using scriptions to produce proteins that then form the building these techniques. The identifi cation of disease-associated blocks of this complex organism is no longer valid. In real- genes in unsolved families no longer requires linkage (-like) ity, the situation is much more complex. Both other genetic techniques. Moreover, with the rapidly growing numbers of factors, like regulatory RNAs (ribonucleic acids) and reported disease-associated genes and gene variants, we are imprinting processes, as well as nongenetic factors like challenged to distinguish the defi nitely disease causing ones metabolites and other environmental infl uences have from (relatively) innocent variants. The latter demands important effects on the fi nal outcome of the information intelligent genomic i n silico solutions, as well as “old-fash- captured in genes. In this paragraph, the basic principles of ioned” wet, but preferably high-throughput laboratory the molecular factors involved will be described and their experimental setups to functionally study the effect of iden- interplay discussed. tifi ed variants. Gene and variant curation remains one of the DNA molecules are composed of four nucleotides, which important goals for the near future. Logically, in the fi eld of all consist of a deoxyribose and a phosphate group, together inherited cardiac disorders, to perform this properly, close forming the sugar-phosphate backbone of the molecule, and collaboration between cardiologists (and other clinical spe- vary in the base side chains adenine (A), guanine (G), cyto- cialists involved), clinical geneticists/genetic counselors, sine (C), or thymine (T) (see Fig. 1 .1 ). These nucleotides are and laboratory specialists is essential. In the following para- connected via phosphodiester linkages and the resulting graphs, the above-mentioned topics and challenges will be nucleic acid strands entwine each other in an antiparallel addressed. fashion, leading to the very stable double-helix structure a b O Guanine (G) N 5’ end NH O N N NH2 NH2 Adenine (A) O P O O N N O H H HO HH N N O Thymine (T) O P O O NH O H H HO HH N O OCytosine (C) O P O O N O H H 5’ HO HH N O O P O O O H H H H O H 5’ O P O 3’ O 3’ end Fig. 1.1 S tructure of DNA. A base (C, T, A, or G) combined with a and the polymerization through phosphodiester linkage, as DNA is read deoxyribose and a phosphate group is called a nucleotide. These nucle- in 5′–3′ direction, the code of this stretch of DNA would read GATC. otides are polymerized through phosphodiester linkage. DNA is read ( c) DNA double-helix structure, the base pairs in the middle are aligned from the 5′ to the 3′ end. (a ) The four bases that make-up the actual around the helical axis. The major and minor grooves are the result of DNA code. Alanine always pairs with thymine with two hydrogen imperfect winding of the helix. Adapted from Clinical Cardiogenetics bonds and cytosine always pairs with guanine using three hydrogen edition 2011 bonds. ( b ) Chemical structure of DNA, showing the sugar backbone

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