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PDF Hosted at the Radboud Repository of the Radboud University Nijmegen 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/2066/105789 Please be advised that this information was generated on 2017-12-06 and may be subject to change. Genetic-Diagnostic Surve y in Intellectually Disabled Individuals from Institutes and Special Schools in Java, Indonesia Genetic-Diagnostic Survey in Intellectually Disabled Individuals from Institutes and Special Schools Farmaditya EP Mundho in Java, Indonesia 978-90-9027320-4 Farmaditya EP Mundhofir ISBN: 978-90-9027320-4 fir Genetic-Diagnostic Survey in Intellectually Disabled Individuals from Institutes and Special Schools in Java, Indonesia Farmaditya EP Mundhofir Genetic-Diagnostic Survey in Intellectually Disabled Individuals from Institutes and Special Schools in Java, Indonesia The studies presented in this thesis are partly funded by RISBIN-IPTEKDOK 2007/2008 program of the Ministry of Health, Republic of Indonesia; Excellent Scholarship (Beasiswa Unggulan), Overseas Study Scholarship (Beasiswa Luar Negeri) of the Directorate General of Higher Education (DGHE) Ministry of Education and Culture Republic of Indonesia and the PhD-fellowship of the Radboud University (RU-fellowship). ISBN/EAN 978-90-9027320-4 © 2013 F.E.P. Mundhofir No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the author. Cover design : FEP Mundhofir Image by : Wardah and Atria from Sekolah Luar Biasa Negeri (State Special School for Intellectual Disability), Semarang, Indonesia Book layout : FEP Mundhofir Graphic design : FEP Mundhofir Printed by : Jentera Int, Yogyakarta, Indonesia Genetic-Diagnostic Survey in Intellectually Disabled Individuals from Institutes and Special Schools in Java, Indonesia 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 20 februari 2013 om 10.30 uur precies door Farmaditya Eka Putra Mundhofir geboren op 25 April 1981 te Jepara, Indonesië Promotoren: Prof. dr. B.C.J. Hamel Mw. prof. dr. S.M.H. Faradz (Universitas Diponegoro, Semarang, Indonesië) Copromotor: Mw. dr. H.G. IJntema Manuscript commissie: Mw. prof. dr. H.M.J van Schrojenstein Lantman – De Valk (voorzitter) Prof. dr. M.A.A.P Willemsen Dr. E.A. Sistermans (Vrije Universiteit, Amsterdam) Genetic-Diagnostic Survey in Intellectually Disabled Individuals from Institutes and Special Schools in Java, Indonesia Doctoral Thesis to obtain the degree of doctor from the Radboud University Nijmegen, on the authority of the Rector Magnificus prof. dr. S.C.J.J. Kortmann, according to the decision of the Council of Deans to be defended in public on February, 20th 2013 at 10.30 hours by Farmaditya Eka Putra Mundhofir Born on April 25, 1981 In Jepara, Indonesia Supervisors: Prof. dr. B.C.J. Hamel Prof. dr. S.M.H. Faradz (Diponegoro University, Semarang, Indonesia) Co-supervisor: Dr. H.G. IJntema Doctoral thesis committee: Prof. dr. H.M.J. van Schrojenstein Lantman - de Valk (chair) Prof. dr. M.A.A.P. Willemsen Dr. E.A. Sistermans (VU University, Amsterdam) A Tribute to My Mother Contents Table of contents List of abbreviations 9 Chapter 1. General introduction, materials and methods, aims and 10 outline of the thesis Chapter 2. Cytogenetic abnormalities in Indonesian ID population 57 A cytogenetic study in a large population of intellectually disabled Indonesians Chapter 3. Fragile-X syndrome in Indonesian ID population 71 Prevalence of Fragile X syndrome in males and females in Indonesia Chapter 4. Subtelomeric deletions and duplications in Indonesian 89 ID population Subtelomeric chromosomal rearrangements in a large cohort of unexplained intellectually disabled individuals in Indonesia: A clinical and molecular study Monosomy 9pter and trisomy 9q34.11qter in two sisters due to a maternal pericentric inversion Chapter 5. The aetiology in a subgroup of ID individuals suspected 117 of having a specific syndrome Mowat–Wilson syndrome: The first clinical and molecular report of an Indonesian patient Molecular analyses on Indonesian individuals with intellectual disability and microcephaly Chapter 6. General discussion and the establishment of a 139 diagnostic protocol for the Indonesian setting Chapter 7 Samenvatting / Summary / Intisari 161 Acknowledgments 167 List of publications 169 Curriculum vitae 170 Appendix 171 Abbreviations List of abbreviations AAIDD American Association on Intellectual and Development Disabilities ADHD Attention deficit hyperactivity disorder ADID Autosomal dominant ID APA American Psychiatric Association APGAR Appearance (skin color), Pulse (heart rate), Grimace (reflex irritability), Activity (muscle tone), and Respiration ARID Autosomal recessive ID ASHG American Society of Human Genetics BAC Bacterial artificial chromosome bp Base pair BP Breakpoint CD Cognitive Disorders CDC United States of America Centers for Disease Control and Prevention CEBIOR Center for Biomedical Research CGH Comparative genome hybridization CMA Chromosomal micro array CNV Copy number variation DD Developmental delay DECIPHER Database of chromosomal imbalance and phenotype in humans using Ensembl Resources DGV Database of Genomic Variants DNA Deoxyribonucleic acid DSM Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders IV Text Revision ECARUCA European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations EDTA Ethylenediaminetetraacetic acid ESHG European Society of Human Genetics FISH Fluorescence in situ Hybridization FoSTes Fork stalling and template switching FXS Fragile-X syndrome HC Head circumference ICBS Indonesian Central Bureau of Statistics ICD International Classification of Diseases ICD Inner canthal distance ICF International Classification of Functioning, Disability and Health ID Intellectual disability IDD Intellectual developmental disorder IEMs Inborn errors of metabolisms 9 Abbreviations IPD Inter pupillary distance IQ Intelligence quotient ISCA International Standard Cytogenomic Array ISS Idiopathic short stature kb Kilobase (thousand base pairs) LWD Leri-Weill Dyschondrosteosis Mb Megabase (million base pairs) MCA Multiple congenital anomalies MLPA Multiplex Ligation-dependent Probe Amplification MODY Maturity-onset diabetes of the young MPS Massive parallel sequencing MR Mental retardation MWS Mowat–Wilson syndrome NAHR Non-allelic homologous recombination NGS Next generation sequencing NHEJ Non-homologous end joining NS-XLID Non syndromic XLID OCD Outer canthal distance OFC Occipital frontal circumference PAR Pseudo autosomal region PCR Polymerase chain reaction PL Palm length PW/AS Prader-Willi/Angelman syndrome qPCR qualitative Polymerase Chain Reaction RUNMC Radboud University Nijmegen Medical Centre SD Standard deviation SNP Single nucleotide polymorphism SNV Single nucleotide variant SRQ Self-reporting questionnaire SSM Slipped strand mispairing THL Total hand length UPD Uniparental disomy UV Unclassified variants WES Whole exome sequencing WHO World Health Organization WHSCR Wolf–Hirschhorn syndrome critical region XCI X-chromosome inactivation XLID X-linked intellectual disability 10 Chapter 1 General introduction, materials and methods, aims and outline of the thesis 1.1 General introduction 1 1.1.1 Definition, classification and epidemiology of intellectual disability (ID) 1.1.2 Aetiology of intellectual disability 1.1.3 Genetic causes of intellectual disability 1.1.4 Neurobiology of genetically based intellectual disability 1.1.5 Indonesia as a field of study 1.2 Materials and methods 1.2.1 Selection of patients and general procedures 1.2.2 Standardized clinical examination 1.2.3 Cytogenetic and molecular investigations 1.2.4 Ethical consideration 1.3 Aims and outline of the thesis General introduction and outline of the thesis 1.1. General introduction 1.1.1 Definition, classification and epidemiology of intellectual disability (ID) Intellectual disability (ID) is a lifelong disability with major impact on individuals’ lives and their families, and is a prevalent disorder worldwide. It has been estimated that the lifetime cost for medical care of a child born with an ID in the United States is roughly as high as US$ 80.000 (Patel et al., 2010; PCPID, 2012). In Indonesia, the lifetime cost of people with ID is not known yet. However, in 2010 the amount of Rp. 3,627 billion (approximately USD 416 million) was allocated from a state budget for people with disability (Irwanto et al., 2010). Having estimated that ID is ~12% of the population of people with disability (Marjuki, 2010; Irwanto et al., 2010), the Indonesian yearly budget for taking care of people with ID is about USD 50 million. The high cost of ID is not only a burden for the society, but for the families as well (Doran et al., 2012). The burden could even get worse if ID is compounded with other disorders, as individuals with ID are at greater risk of developing secondary health problems (Maiano, 2011). Some reports highlighted the existence of co- morbidity of ID and other conditions such as mental disorders and obesity (Einfeld et al., 2011; Maiano, 2011). The terminology to describe ID has changed from idiocy, feeble
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