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Gene Identification in Intellectual Disability 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/2066/107980 Please be advised that this information was generated on 2021-09-29 and may be subject to change. Gene Identification in intellectual disability Janneke H.M. Schuurs-Hoeijmakers IGMD Gen® identifseatson in intelleotual dïsabüty Janneke H.M. Schuurs-Hoeijmakers Cover design and layout by In Zicht Grafisch Ontwerp, Arnhem Printed and bound by Ipskamp Drukkers, Enschede ISBN 978-90-9027086-9 Copyright © 2012 J.H.M. Schuurs-Hoeijmakers All rights reserved. No parts of this publication may be reproduced, stored in a retrieval system of any nature, or transmitted in any form or by means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the holder of the copyright. Gen© identifioation in intellectual disability 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 donderdag 20 december 2012 om 13u00 precies door Johanna Hendrica Maria Schuurs-Hoeijmakers geboren op 26 maart 1982 te Zevenhuizen (ZH), Nederland Promotoren Prof.dr H.G. Brunner Prof.dr. H. van Bokhoven Copromotoren Dr. B.B.A. de Vries Dr. A.P.M. de Brouwer Manuscriptcommissie Prof.dr. M.A.A.P. Willemsen (voorzitter) Prof.dr. M.H. Breuning (Leids Universitair Medisch Centrum, Leiden) Prof.dr. M. Nordenkjöld (Karolinska Instituut, Stockholm, Zweden) Paranimfen Wieteke Faber-Hoeijmakers Anneke Vulto-van Silfhout Table of contents Chapter 1 Intellectual disability: a general introduction 7 Chapter 2 Homozygosity mapping in outbred families with 33 Mental Retardation Chapter 3 Identification of recessive pathogenic alleles in small 47 sibling families with intellectual disability Chapter 4 Mutations in DDHD2, encoding an intracellular 79 phospholipase A-i, cause a recessive form of complex Hereditary Spastic Paraplegia Chapter 5 Recurrent de novo mutations in PACS1 cause defective 105 cranial neural crest migration and define a recognizable intellectual disability syndrome Chapter 6 Discussion and future perpective 121 Summary 139 Samenvatting 143 Reference List 147 Dankwoord | Acknowledgements 161 Curriculum Vitae 167 List of publications 169 List of abbreviations 173 Colorfigures 177 Thesis series of the Institute for Genetic and Metabolic Disease 207 Table of contents Chapter 1 Intellectual disability: a general introduction 7 Chapter 2 Homozygosity mapping in outbred families with 33 Mental Retardation Chapter 3 Identification of recessive pathogenic alleles in small 47 sibling families with intellectual disability Chapter 4 Mutations in DDHD2, encoding an intracellular 79 phospholipase A-i, cause a recessive form of complex Hereditary Spastic Paraplegia Chapter 5 Recurrent de novo mutations in PACS1 cause defective 105 cranial neural crest migration and define a recognizable intellectual disability syndrome Chapter 6 Discussion and future perpective 121 Summary 139 Samenvatting 143 Reference List 147 Dankwoord | Acknowledgements 161 Curriculum Vitae 167 List of publications 169 List of abbreviations 173 Colorfigures 177 Thesis series of the Institute for Genetic and Metabolic Disease 207 Intellectual disability: a general introduction C H A P T E R 1 1.1 Definition 9 1.2 Prevalence 11 1.3 Inherited ID and etiology 12 1.4 Techniques fordetection ofgenetic causes oflD: a historica! overview 13 1.4.1 Karyotyping 13 1.4.2 Targeted chromosome analysis 14 1.4.3 Array CGH: emerging genomic disorders 15 1.4.4 Array CGH: gene discovery 16 1.4.5 Gene discovery by linkage studies 18 1.4.6 Massive parallel sequencing 19 1.4.6.1 Massive parallel sequencing: a revolution for hu man genetics 19 1.4.6.2 The coding sequences of the genome: the exome 19 1.4.6.3 Gene discovery in ID syndromes by use of exome sequencing 22 1.4.6.4 Massive parallel sequencing for autosomal gene Identification 23 in non-syndromic ID 1.4.6.5 Massive parallel sequencing for recessive gene 'Identification 26 1.4.6.6 Exome sequencing in diagnostics 27 1.5 Scope and outline ofthis thesis 28 1.5.1 Why do we study genetics of ID? 28 1.5.2 Aims 28 1.5.3 How did we study genetics underlying ID? 28 INTELLECTUAL DISABILITY: A GENERAL iNTRODUCTION intellectual disability: a genera! introduction 1.1 Definition The brain is one of the most complex and intriguing human organs. lts fine-tuned development, cellular connectivity and plasticity are crucial for normal functioning. The outcome of aberrant brain development and/or aberrant interaction between brain cells can clinically present as intellectual disability (ID). ID comprises a group of clinically and etiologically heterogeneous cognitive disorders that is primarily characterized by defects and subsequent malfunctioning of the brain. Clinicians often make a subdivision of syndromic or specific versus non-syndromic or non- specific forms depending on the presence or absence, respectively of additional clinical features accompanying ID, such as dysmorphic, metabolic, neuromuscular or psychiatrie features and congenital malformations1. Terminology to describe individuals with ID has been changed frequently. Names used in the past for those with ID include idiot, imbecile, feeble-minded, mentally handicapped and mentally retarded2. Over the last few years there has again been a change in terminology brought about by President Obama signing Rosa’s law on the 5th of October 2009, thereby replacing several instances of ‘mental retardation’ in law with ‘intellectual disability'2 (Box 1). Box 1 The introduction of Rosa's Law replaces mental retardation for intellectual disability S. 2781 (111th): Rosa’s Law 111,h Congress, 2009-2010 A bill to change references in Federal law to mental retardation to references to an intellectual disability, and to change references to a mentally retarded individual to references to an individual with an intellectual disability. Introduced: November 17th, 2009 Sponsor: Sen. Barbara Mikulski [D-MD] Status: Signed by the President, October 5lh, 2009 9 C H A P T E R 1 For formal clinical diagnosis and classification of ID, mainly three systems are in use: the International Statistical Classification of Diseases and Related Health Problems (ICD-10)3from the World Health Organization, the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR)4 from the American Psychiatrie Association and the definition of the American Association on Intellectual and Developmental Disabilities (11th edition, AAIDD)5. All definitions state a substantial impairment in both cognitive functioning and adaptive behavior, originating in the developmental period (defined as before 18 years of age). Cognitive or intellectual functioning refers to general mental capacities, such as learning, reasoning and problem solving, and can be measured by intelligence quotiënt (IQ)-testing, where 100 IQ-points is the mean and an IQ-score <70 is indicative of substantial impairment in intellectual functioning, Several tests have been developed for the calculation of intelligence (reviewed by Deary et al6.). One of the most widely used tests for IQ assessment was devised by Wechsler, comprising preschool, child and adult versions. IQ measurements give an indication of severity of ID, frequently subdivided into four categories: mild (IQ 50-70), moderate (IQ 35-50), severe (IQ 20-35) and profound ID (IQ <20) (Table 1). The AAIDD does not subdivide ID based on IQ-score and rather concentrates on the nature of needed support: intermittent, Table 1 Subdivision of severity of ID based on IQ measurement DSM-IV-TR classification ICD-10 classification Terminology code IQ level code IQ level mild 317 50-55-to 70 F70 50-69 moderate 318.0 35-40 to 50-55 F71 35-49 severe 318.1 20-25 to 35-40 F72 20-34 profound 318.2 <20-25 F73 <20 Nole- DSM-IV-TR takes into account a measurement error of (ive points. as this is inherent to intelligence testing limited, extensive or pervasive. Adaptive behavior consists of (i) conceptual skills, such as language and literacy and self-direction, (ii) social skills, such as inter- personal skills, social responsibility, self-esteem, social problem solving and the ability to follow rules, and (iii) practical skills, such as personal care and occupational skills. In short, for clinicians, the combined presentation of impairment in (one of) these areas of adaptive behavior and cognitive impairment are the clinical hallmarks on which the diagnosis of ID is based. 1 0 INTELLECTUAL DISABILITY; A GENERAL INTRODUCTION 1.2 PrevaSence Intelligence of the (healthy) population follows a normal or Gaussian distribution, with an IQ approximately in between 50 to 150 (Figure 1), indicating that an IQ < 70 (<-2SD) will be observed as normal variation within the population. However, already observed and described in 1967 by Zigler7, this is not a completely representative image of the empirical distribution of intelligence since people with ID, where a physiological defect is suspected to underly the ID phenotype, fall for most part outside the range of normal intelligence and represent a second distribution curve in addition to the Gaussian curve with a considerably lower mean IQ (Figure 1)7. An appropriate representation of intelligence distribution encompasses two distribution curves, a normal distribution curve with a mean of 100 IQ points for the 'healthy' population, representing polygenic or multifactorial intelligence distribution. And a second curve with an mean around 35, representing a group of people with ID due to pathophysiological defects, such as perinatal and monogenetic causes. To estimate the prevalence of ID, intelligence and its distribution is only one of the factors that needs to be considered. Determining the prevalence of ID is not straightforward as several factors influencing estimation and interpretation need to be taken into account1-8, not in the least the above mentioned different definition systems that are in use to diagnose individuals with ID.
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