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UNIVERSITY of CALGARY a Novel Neurodevelopmental Disorder Within the Hutterite Population Maps to 16P and a Possible Causative M

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UNIVERSITY OF CALGARY A Novel Neurodevelopmental Disorder within the Hutterite Population Maps to 16p and a Possible Causative Mutation in THOC6 was Identified by Chandree Lynn Beaulieu A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF MEDICAL SCIENCES CALGARY, ALBERTA JANUARY, 2010 © Chandree Lynn Beaulieu Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-62049-6 Our file Notre référence ISBN: 978-0-494-62049-6 NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l’Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L’auteur conserve la propriété du droit d’auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author’s permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n’y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. ABSTRACT The Hutterites are a genetically isolated group; their population numbers over 40,000, the majority of whom are descendants of 89 founders. An autosomal recessive neurodevelopmental disorder was identified in four patients from two Hutterite families. The patients have distinctive facial features, congenital malformations of the heart and genitourinary system, borderline microcephaly, and learning disability. An identity-by-descent mapping approach was used to identify the locus for this disorder. A 50K-SNP microarray identified a single, homozygous region on 16p13.3 shared between the patients. Microsatellite markers genotyped for all available family members refined the locus to a region of 5.1 Mb containing 173 genes. No other recessive disorders with similar clinical features are currently mapped to this region. Genes within the region were prioritized using data mining and expression microarrays. Ninety-seven genes were sequenced. A homozygous variant in THOC6 (p.G46R) was identified and evidence suggests that this variant is disease-causing. ii ACKNOWLEDGEMENTS Thank you to everyone for making my Masters studies a wonderful experience. Thank you to my supervisor Dr. Jillian Parboosingh. You took me into the lab as a quiet summer student with very little previous lab experience and provided me with the support and environment I needed. Your support in all aspects throughout this process has been invaluable. Thank you for the effort you put in to provide me with exposure to a variety of techniques and concepts making this a good learning experience for me. Thank you to the members of my supervisory committee Dr. Micheil Innes and Dr. Paul Mains. Dr. Micheil Innes thanks for your discussions on the patients’ characteristics, the Hutterite population, and prioritization of genes as well as your encouragement. Dr. Paul Mains thanks for your questions guiding me to look further into concepts and mechanisms. Thank you Dr. Kym Boycott for your support and suggestions in all aspects of the project and for your mentorship. Thank you Dr. Fred Biddle for your role in getting me into this lab, our conversations, your confidence in my abilities, and always pushing me to a higher level. Thank you to all the students and fellows who I have had the opportunity to work with in the lab. Thank you Catrina Loucks and David Redl; you have been great to work with and thanks for all our discussions and your help. Thank you Dr. Patrick Frosk for suggestions on using genomic databases, mapping, and prioritization. Thank you Dr. Ryan Lamont for advice and information. Thank you Stephanie Desmarais, Dr. Tanya Gillian, Megan Black, Danielle Lynch, and Jack Novovic. Thank you to all the medical genetics residents for discussions and opportunities to learn and be involved in other projects. Dr. David Dyment thanks for showing me statistical linkage analysis programs and Dr. Oana Caluseriu thanks for the mentorship. Thank you to all the staff at the Alberta Children’s iii Hospital Molecular Diagnostic Laboratory for everything you have taught me and for your company. Dana Forrest thanks for training me on experimental techniques. Thanks to everyone in the Molecular and Medical Genetics, Genes and Development Research Group the opportunity to participate in Journal Club, Research in Progress, and Medical Genetics Rounds and thanks for all the fun events. Thank you to the Southern Alberta Microarray Facility where I performed the expression microarrays (and Dr. Xiuling Wang for her help). Thank you to Dr. Erik Puffenberger for performing the SNP microarrays. Thank you to Dr. Carol Ober’s lab for genotyping the Hutterite controls. Thank you to those who had clinical involvement with the patients: Dr. Kym Boycott, Dr. Mike Innes, Dr. Ross McLeod, Dr. Brian Lowry, Dr. Bea Fowlow, Jackie Morris, Carol Farr, and Rachelle Bistretzan. Thank you to the patients and their families for their enthusiastic participation in this study. This study was supported by an Alberta Children’s Hospital Foundation Grant and I was supported by the UofC CIHR Training Program in Genetics, Child Development, and Health. Thanks also to the sponsors of the William H. Davies Scholarship, Queen Elizabeth II Scholarship, Medical Science Graduate Program Award, Graduate Conference Travel Grant, and Alberta Graduate Student Scholarship. Thanks to everyone at Canon US Life Sciences who welcomed me as part of their team for an internship this past summer. Thank you to all of my professors and teachers. Thank you to my friends; you are all wonderful. And, a very special thanks to my parents and family for their constant support throughout all of my studies. iv TABLE OF CONTENTS ABSTRACT ......................................................................................................................... ii ACKNOWLEDGEMENTS...............................................................................................iii TABLE OF CONTENTS.................................................................................................... v LIST OF TABLES ............................................................................................................ vii LIST OF FIGURES .........................................................................................................viii LIST OF ABBREVIATIONS............................................................................................ ix INTRODUCTION............................................................................................................... 1 Importance of recessive disorders ................................................................................. 1 The Hutterite population................................................................................................ 2 Novel neurodevelopmental disorder.............................................................................. 5 Available patient resources........................................................................................... 5 Clinical features ............................................................................................................ 7 Comparison to other disorders ................................................................................... 10 Identity-by-descent mapping........................................................................................ 11 Gene prioritization strategies....................................................................................... 14 SNP arrays ..................................................................................................................... 17 A homozygous region of interest was identified by genome-wide SNP analysis ........ 17 Copy number from SNP arrays ................................................................................... 20 OBJECTIVES AND RATIONALE................................................................................. 21 METHODS ........................................................................................................................ 23 DNA extraction.............................................................................................................. 23 Fine mapping with
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