Clinical Cardiogenetics

391 Pages·2016·18.038 MB·English

by  Hubert F. Baars, Pieter A. F. M. Doevendans, Arjan C. Houweling, J. Peter van Tintelen (eds.)

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
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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