University of Groningen. Congenital heart defects and pulmonary arterial hypertension Frederikse, Wilhelmina
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1 University of Groningen Congenital heart defects and pulmonary arterial hypertension Frederikse, Wilhelmina 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: 2014 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Kerstjens-Frederikse, W. (2014). Congenital heart defects and pulmonary arterial hypertension: Genes, environment and heredity University of Groningen 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). 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): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:
2 Congenital Heart Defects and Pulmonary Arterial Hypertension Genes, Environment and Heredity Mieke Kerstjens-Frederikse
3 Congenital Heart Defects and Pulmonary Arterial Hypertension Genes, Environment and Heredity ISBN (book) ISBN (Ebook) Author: W.S. Kerstjens-Frederikse Cover design: Machteld Hardick, mhardick.nl Lay-out: Peter van der Sijde, proefschriftgroningen.nl Printed by: Ipskamp Drukkers Financial support by the Graduate School of Medical Sciences of the University Medical Center Groningen and by the University of Groningen for the publication of this thesis is gratefully acknowledged. Copyright W.S.Kerstjens-Frederikse. All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without written permission from the author.
4 Congenital Heart Defects and Pulmonary Arterial Hypertension Genes, Environment and Heredity Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 2 juli 2014 om uur door Wilhelmina Sophia Frederikse geboren op 12 februari 1958 te Apeldoorn
5 Promotores Prof. dr. R.M.W. Hofstra Prof. dr. R.M.F. Berger Beoordelingscommissie Prof. dr. D. Bonnet Prof. dr. H.G. Brunner Prof. dr. M.P. van den Berg
6 Paranimfen Karin Y. van Spaendonck-Zwarts Huib A.M. Kerstjens
7
8 TABLE OF CONTENTS List of abbreviations 8 Genetic Terminology 10 Chapter 1 General Introduction 13 PART I GENES, ENVIRONMENT AND HEREDITY IN CONGENITAL HEART DEFECTS Chapter 2 Genetic aspects of congenital heart defects. 33 Translated and adapted from chapter 23 In: Aangeboren hartafwijkingen bij volwassen. Editors B.J.M. Mulder, P.G. Pieper, F.J. Meijboom, J.P.M. Hamer. Bohn Stafleu van Loghum, 3rd ed Chapter 3 Left ventricular outflow tract obstruction: should cardiac screening be 45 offered to first degree relatives? Heart 2011;97: Chapter 4 Cardiovascular malformations caused by NOTCH1 mutations do not 59 keep left: data on 427 LVOTO probands and their families Submitted Chapter 5 A homozygous mutation in Smoothened, a member of the (SHH)-GLI 79 pathway, is involved in human syndromic atrioventricular septal defect. Submitted Chapter 6 The cardiac phenotype in patients with a CHD7 mutation. 97 Circ Cardiovasc Genet. 2013;6: Chapter 7 Combined adverse effects of maternal smoking and high body mass 113 index on heart development in offspring: evidence for interaction? Heart. 2012;98: PART II HEREDITY IN PULMONARY ARTERIAL HYPERTENSION Chapter 8 TBX4 mutations (small patella syndrome) are associated with 129 childhood-onset pulmonary arterial hypertension. J Med Genet. 2013;50: Chapter 9 Pulmonary Arterial Hypertension in adults with isolated atrial septal 147 defects: the role of BMPR2-mutations and outcome after defect closure Submitted Chapter 10 Summary, discussion and future perspectives 161 Nederlandse samenvatting 177 List of authors and affiliations 183 Dankwoord 187 Curriculum vitae 193 List of publications 195
9 Abbreviations LIST OF ABBREVIATIONS acgh ASD AVSD AI AV AVR AVS BAV BMI CDS CHA chr CHD CI CNV COA DF DILV DMP DORV EMT FISH GDM HLHS HPAH IPAH LVNC LVOTO MAF MCA MLPA MR MVS MVR NCA NYHA array comparative genomic hybridisation atrial septal defect atrial ventricular septal defect aortic valve insufficiency aortic valve aortic valve replacement aortic valve stenosis bicuspid aortic valve body mass index coding sequences congenital heart anomalies chromosome congenital heart defect confidence interval chromosomal numerical variations coarctation of the aorta dysmorphic features double inlet left ventricle dorsal mesenchymal protrusion double outlet right ventricle epithelial-to mesenchymal-transition fluorescence in situ hybridization gestational diabetes mellitus hypoplastic left heart syndrome hereditary pulmonary arterial hypertension idiopathic pulmonary arterial hypertension left ventricular non-compaction left ventricular outflow tract obstructions, including BAV, AVS, COA, HLHS minor allele frequency multiple congenital anomalies multiplex ligation-dependent probe amplification mental retardation mitral valve stenosis mitral valve replacement non-cardiac congenital anomalies New York Heart Association 8
10 Abbreviations OR PAH PDA PCR PA PH PVD PVR PVS RHC RVOTO RVF RVSP SHH SLOS SNP SPS SVAS TA TGA TOF VSD WGA odds ratio pulmonary arterial hypertension persistent ductus arteriosus polymerase chain reaction pulmonary valve atresia pulmonary hypertension pulmonary valve disease pulmonary vascular resistance pulmonary valve stenosis right heart catheterization right ventricular outflow tract obstructions right ventricular failure right ventricular systolic pressure sonic hedgehog Smith-Lemli-Opitz syndrome single nucleotide polymorphism small patella syndrome supravalvular aortic stenosis truncus arteriosus transposition of the great arteries Fallot s tetralogy ventricular septal defect whole genome array 9
11 Genetic Terminology GENETIC TERMINOLOGY There are many textbooks and websites on genetics that explain the terms and techniques below, but I have added these explanations to help physicians non-geneticists who may read this thesis. Allele: Because all DNA in humans is present in duplo (except for the X- and Y chromosomes in males) the term allele is used to distinguish between the two copies. In this context, the maternal allele is the allele inherited from the mother and the paternal allele is from the father. Complex (or multifactorial) inheritance: Complex diseases are diseases caused by a combination of inherited and non-inherited factors. The inherited component is polygenic, meaning that variations in different genes, on different chromosomes contribute to the disease phenotype, whether or not in combination with known or unknown environmental factors. In other words: multiple risk factors accumulate and a disease will occur only after they reach a certain threshold. The essential difference from monogenic, Mendelian inheritance is that more than one gene causes the disease. Epigenetics: Epigenetics concerns factors influencing the expression of genes in a reversible way, without changing the nucleotide sequence of the DNA in the nucleus. Exome: The total of protein coding DNA (approximately 1.5% of the genome). Expression: The clinical expression of a genetic predisposition is the way the disease presents. Variable expression means that carriers of a mutation have different symptoms of a disease. A second use of the term is to designate the expression of genes in certain tissues: whether or not a gene is translated to protein. Gene: A stretch of DNA containing the code for one protein. A gene has exons and introns. The introns are spliced-out during transcription to RNA and the exons contain the code for the protein. Genome: The total of DNA a person inherits from one parent. Human cells are diploid and therefore contain 2 genomes, one from each parent. Genomic imprinting: Imprinting is the epigenetic reversible modification of genes or regions in the genome in the parental gametes, leading to functionally different expression of the two alleles. In other words: the expression of a part of the genome depends on the gender of the transmitting parent. Imprinting may be involved in monogenic as well as complex inheritance. Imprinting may explain why the recurrence of congenital heart defects (CHD) is more frequent in the offspring of females with CHD than in the offspring of males with CHD. Mendelian inheritance: Mendelian inheritance is the form of inheritance according to Mendel s laws, which state that a certain disease is caused by a mutation in one or both alleles of a gene. It is therefore designated monogenic inheritance. The pattern of inheritance is autosomal or X-linked and either dominant or recessive. Large non-coding RNAs (LncRNAs): LncRNAs are large molecules of non-coding RNA of more than 200 nucleotides, regulating gene expression through several mechanisms. They are reported to play 10
12 Genetic Terminology a role in cardiac development and disease. Micro-RNAs (mirnas): mirnas are small molecules of non-coding RNA of approximately 22 nucleotides, repressing translation to proteins by binding to messenger RNA. It has been proven that mirnas play an important role in heart development. Penetrance: The penetrance of a genetic predisposition is the proportion of persons expressing the disease. Reduced penetrance means that a mutation in a gene gives rise to symptoms in only some of the mutation carriers but not in others. Some genetic techniques Array-comparative genome hybridization (acgh): acgh is a molecular technique to compare the amount of DNA at many different points in the genome, allowing the detection of small deletions and duplications of genetic material at random positions. The test can be performed on DNA that has been isolated from EDTA blood or a tissue biopsy. Fluorescence in situ hybridization (FISH): FISH may be used if one expects to find a deletion at a specific, known position on a chromosome. Metaphase nuclei are hybridized with a specific probe labelled with a fluorescent dye. Fluorescent microscopy is used to determine whether the two copies of a specific DNA sequence are present or not. The test can be performed on cells from a heparinised blood sample or from a tissue biopsy. Karyotyping: Karyotyping or chromosome analysis describes the number and appearance of chromosomes in metaphase nuclei under a normal-light microscope. It detects numerical chromosomal anomalies (trisomy, monosomy) and large structural anomalies (translocations, large deletions, duplications and inversions). It can be performed on cells isolated from heparinized blood or tissues biopsies. Next generation sequencing (NGS): Sequencing means determining the order of the nucleotide in a DNA molecule. NGS is a method for parallel sequencing of large numbers of DNA templates, reducing the amount of time and money needed for the tests. Several systems are available, all using fragmented DNA of a specific sample, binding to method-specific linkers. The automation enables testing of a complete exome or even genome of an individual. These methods facilitate gene finding in research settings and are now also being implemented in diagnostics. The tests can be performed in DNA that has been isolated from EDTA blood or a tissue biopsy. Sanger sequencing: Sequencing means determining the order of the nucleotide in a DNA molecule. Sanger sequencing is the classical method ( first generation sequencing ) of analysing DNA by adding small amounts of labelled dideoxynucleotides (ddntps) to the four normal nucleotides, creating labelled stops in the DNA string. The method has been adjusted to gain speed by using coloured labels and capillary and laser detection instead of fluorescent and radioactive labels, gels and fluorescence or radioactivity detection. The tests can be performed in DNA that has been isolated from EDTA blood or a tissue biopsy. 11
13 Genetic Terminology Single Nucleotide Polymorphism (SNP)array: SNP array is a molecular technique to compare nucleotides at many different points in the genome from a patient with reference DNA. It can be used for several purposes, for example for the detection of small deletions and duplications of genetic material at random positions. The test can be performed on DNA that has been isolated from EDTA blood or a tissue biopsy. 12
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