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Genotype-Phenotype Studies in Rare Chromosome Aberrations

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Genotype-Phenotype Studies in Rare Chromosome Aberrations PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/115714 Please be advised that this information was generated on 2021-09-25 and may be subject to change. Genotype-phenotype studies in rare chromosome aberrations Ilse Feenstra The research described in this thesis was performed at the Department of Human Genetics, Radboud University Nijmegen Medical Centre, the Netherlands. Head: Prof. dr. H.G. Brunner. The research was funded by the Dutch Brain Foundation, grant 12F04.25, and by the the Fifth Framework Program of the European Union entitled “Quality of Life and Management of Living Resources” (project number QLRI-CT-2002-02746). Cover Esther Ris, Proefschriftomslag.nl Layout Renate Siebes, Proefschrift.nu Printed by Ipskamp Drukkers B.V. This thesis has been printed on FSC-certified paper originating from well-managed and sustainable sources ISBN 978-94-90791-18-6 © 2013 I. Feenstra, Nijmegen All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without the permission of the author, or, when appropriate, of the publishers of the publications. Genotype-phenotype studies in rare chromosome aberrations PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de Rector Magnificus prof. mr. S.C.J.J. Kortmann, volgens besluit van het college van decanen in het openbaar te verdedigen op woensdag 8 mei 2013 om 13.30 uur precies door Ilse Feenstra geboren op 12 oktober 1975 te Heemskerk Promotoren: Prof. dr. H.G. Brunner Prof. dr. C.M.A. van Ravenswaaij-Arts (Universitair Medisch Centrum Groningen) Manuscriptcommissie: Prof. dr. J.M.G. van Vugt (voorzitter) Prof. dr. H.A.M. Marres Dr. E.K. Bijlsma (Leids Universitair Medisch Centrum) Voor mijn ouders CONTENTS Abbreviations 9 Chapter 1 General introduction and outline of this thesis 11 Chapter 2 The importance of good data storage 2.1 European Cytogeneticists Association Register of Unbalanced 37 Chromosome Aberrations (ECARUCA); an online database for rare chromosome abnormalities Chapter 3 Using high resolution genome-wide techniques in the pre- and postnatal diagnostic setting 3.1 Balanced into array: genome-wide array analysis in 54 patients 57 with an apparently balanced de novo chromosome rearrangement and a meta-analysis 3.2 Non-targeted whole genome 250K SNP array analysis as 83 replacement for karyotyping in fetuses with structural ultrasound anomalies: evaluation of a one-year experience Chapter 4 Various clinical aspects of the 18q deletion syndrome 4.1 Genotype-phenotype mapping of chromosome 18q deletions by 103 high-resolution array CGH: an update of the phenotypic map 4.2 Neuropsychiatry and deletions of 18q; case report and diagnostic 121 considerations 4.3 Cardiac anomalies in individuals with the 18q deletion syndrome; 131 Report of a child with Ebstein anomaly and review of the literature Chapter 5 Single gene disorders and 18q 5.1 Disruption of the TCF4 gene in a girl with mental retardation but 145 without the classical Pitt-Hopkins syndrome 5.2 Disruption of Teashirt Zinc Finger Homeobox 1 is associated with 159 congenital aural atresia in humans Chapter 6 Discussion and future directions 175 Summary 196 Samenvatting 201 Curriculum Vitae 208 List of publications 209 ABBREVIATIONS AF Amniotic Fluid BAC Bacterial Artificial Chromosome BAEP Brainstem Auditory Evoked Potentials BAHA Bone Anchored Hearing Aid BERA Brainstem Evoked Response Audiometry bp base pair BP breakpoint CAA Congenital Aural Atresia CHD Congenital Heart Disease CGH Microarray-based Comparative Genomic Hybridization CHARGE Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness CNV Copy Number Variation CT Computer Tomography DECIPHER DatabasE of Chromosome Imbalance and Phenotype in Humans Using Ensembl Resources DNA Desoxyribo Nucleic Acid DSM Dense Surface Models ECARUCA European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations EEG ElectroEncephaloGraphy FISH Fluorescent In Situ Hybridization fMRI functional Magnetic Resonance Imaging GH Growth Hormone ID Intellectual Disability IUGR Intra Uterine Growth Retardation IQ Intelligent Quotient kb kilobase (thousand base pairs) MACRs malformation-associated chromosome regions Mb Megabase (million base pairs) MCA Multiple Congenital Abnormalities MLPA Multiplex Ligation-dependent Probe Amplification 9 MR Mental Retardation MRI Magnetic Resonance Imaging NT Nuchal Translucency OMIM Online Mendelian Inheritance in Man PCR Polymerase Chain Reaction PHS Pitt Hopkins Syndrome QF-PCR Quantitative Fluorescence Polymerase Chain Reaction qPCR quantitative Polymerase Chain Reaction SD Standard Deviation SMS Smith Magenis Syndrome SNP Single Nucleotide Polymorphism TOP Termination Of Pregnancy TSH Thyroid Stimulating Hormone UCSC University of California, Santa Cruz WBS Williams-Beuren Syndrome WHS Wolf-Hirschhorn Syndrome WHSCR-1 WHS critical region 1 WHSCR-2 WHS critical region 2 10 chapter 1 General introduction and outline of this thesis Based on: Ilse Feenstra, Han G. Brunner and Conny M.A. van Ravenswaaij-Arts Cytogenetic genotype-phenotype studies: Improving genotyping, phenotyping and data storage Cytogenet Genome Res 115:231–239 (2006) Chapter 1 From microscope to microarray The genetic information is carried by DNA, which is packaged in chromosomes, tread-like structures located in the nucleus of the cell. Each chromosome is made up of DNA tightly coiled many times around histones that support its structure. The number and appearance of chromosomes in the nucleus of a eukaryotic cell is referred to as the karyotype. In 1956, the total number of chromosomes per cell in humans was visualized by microscope and determined to be 46, consisting of 22 pairs of autosomes and a single pair of sex chromosomes. 1 A few years later the underlying genetic cause of Down syndrome was revealed to be an extra chromosome 21. 2 It appeared to be that chromosomal rearrangements are an important cause of distinctive and recognizable clinical phenotypes. Subsequently, other numerical chromosomal aberrations have been detected in patients presenting with an overlapping phenotype, including Patau syndrome (trisomy 13) 3, Edwards syndrome (trisomy 18) 4, Turner syndrome (45,X) 5 and Klinefelter syndrome (47,XXY). 6 With the implementation of chromosome banding techniques, not only numerical but also structural rearrangements and partial chromosome aberrations could be identified. 7-9 This has led to the identification and categorization of numerous unbalanced chromosome aberrations in individuals with intellectual disability and/or congenital anomalies such as deletions and duplications, as well as inversions and translocations. 10 However, small chromosome aberrations of less than 5 Mb cannot be detected by standard karyotyping. The introduction of fluorescence in situ hybridization (FISH) techniques and multiplex ligation-dependent probe amplification (MLPA) allowed for the detection of small, submicroscopic cytogenetic rearrangements. 11,12 Yet, both FISH and MLPA approaches are targeted and, as such, only allow analysis of specific chromosome regions correlated to a suspected clinical syndrome, which can be recognized by characteristic clinical features. The cytogenetic origin of a number of well-known syndromes has been revealed by extensive cytogenetic examination of large cohorts of individuals with similar clinical characteristics, for example velo-cardio-facial syndrome, caused by a interstitial deletion of 22q11.2, Williams-Beuren (7q11.23) and Miller-Dieker syndrome (17p13.3). 13-19 Most often the submicroscopic aberration was revealed after association of balanced translocations with the clinical phenotype. 20,21 However, in the majority of patients with developmental delay a normal karyotype is seen and no specific submicroscopic syndrome diagnosis can be made. The gap between the demand 12 General introduction and outline of this thesis for whole genome analysis on one side and the possibility to detect small aberrations on the other side has been closed by the introduction of microarray techniques, also referred to as 1 molecular karyotyping. 22-24 This whole genome technology is able to detect chromosomal aberrations at a resolution beyond the detection level of conventional karyotyping and has therefore been one of the most significant changes in the diagnostic process of individuals with intellectual disability and/or congenital anomalies. 25-27 An overview of current cytogenetic and molecular techniques used in clinical cytogenetics is given in Table 1.1. Using new molecular karyotyping techniques, many new microdeletion and microduplication syndromes have been identified and the list is still growing. 28-31 Whereas in the pre- microarray era a clinical syndrome diagnosis was made first, followed by a confirmation on chromosome level, the expansion of high resolution whole genome techniques led to a shift from the original ‘phenotype first’ approach, to a ‘genotype-first’ approach, a development also labeled as ‘reverse phenotypics’. 32 High resolution genotyping rapidly found its way as a first screening test in the daily diagnostic process of individuals with intellectual
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