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Whole Exome Sequencing Analysis of Intracranial WHOLE EXOME SEQUENCING ANALYSIS OF INTRACRANIAL ANEURYSM IN MULTIPLEX FAMILIES FROM NEWFOUNDLAND AND LABRADOR by © Amy E. Powell A thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Master of Science Discipline of Genetics, Faculty of Medicine Memorial University of Newfoundland May 2016 St. John’s Newfoundland and Labrador Abstract Intracranial aneurysm (IA) is a vascular condition characterized as a saccular dilatation of the cerebral artery wall. The purpose of this study was to identify genetic variants that cause susceptibility to IA in two multiplex families from Newfoundland and Labrador. Whole exome sequencing was completed for 12 affected individuals from families R1352 and R1256. A filtering strategy was then implemented to identify and prioritize rare variants that were shared by multiple affected family members. In family R1352, two variants were identified as top candidates: C4orf6 c.1A>G, and GIGYF2 c.3494A>G. Both were present in 6/7 exomes from the family, and passed all filtering steps. In family R1256, SPDYE4 c.103C>T was identified as a variant of interest, as it segregated in 10/11 affected individuals. Though each variant exhibited incomplete segregation, all three were absent from 100 local population controls. The absence of a definitive candidate variant in the exome suggests that further study is necessary to gain better understanding of the genetic etiology of this disease. ii Acknowledgements First, I would like to thank my supervisor, Dr. Michael Woods, for his guidance, knowledge and mentorship throughout my research project. I would also like to thank my supervisory committee members, Drs. Bridget Fernandez and Sevtap Savas, for their support and assistance throughout the past two years. Thank you to Dr. Fernandez, Barbara Noble, and the entire team involved in patient recruitment and the collection of clinical information for this project. Thank you to the study participants and their families, without whom this research would not be possible. As well, thank you to our funding agencies: the Heart and Stroke Foundation of Canada, and the Medical Research Fund from Memorial University, for providing financial support. I would also like to thank the former and current members of the Woods lab, Robyn Byrne and Daniel Evans, for their valued input and help with learning laboratory techniques. Thank you to the students, staff and faculty of the Discipline of Genetics, especially Deborah Quinlan, for their support and advice. Finally, thank you to my parents and family, for their continued encouragement throughout my academic career. iii Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................ iii Table of Contents ............................................................................................................... iv List of Tables .................................................................................................................... vii List of Figures .................................................................................................................... ix List of Abbreviations ......................................................................................................... xi List of Appendices ........................................................................................................... xiii 1. Introduction ..................................................................................................................... 1 1.1 Intracranial Aneurysm .............................................................................................. 1 1.1.1 Aneurysm, Subarachnoid Hemorrhage, and Stroke ........................................... 1 1.1.2 Risk Factors for IA Development and Rupture ................................................. 3 1.1.3 Screening and Treatment for IA ........................................................................ 5 1.1.4 Pathophysiology ................................................................................................. 7 1.2 The Genetic Contribution to IA .............................................................................. 12 1.2.1 Preliminary Evidence ....................................................................................... 12 1.2.2 Family-Based Studies ...................................................................................... 15 1.2.3 Candidate Gene Studies ................................................................................... 19 1.2.4 Genome-Wide Association Studies ................................................................. 21 1.2.5 Recent Strategies for IA Research ................................................................... 27 1.3 Studying IA in Newfoundland and Labrador.......................................................... 32 1.3.1 Heritable Disease Research in NL ................................................................... 32 1.3.2 Previous Work Completed ............................................................................... 33 1.3.3 Utilizing Whole Exome Sequencing ................................................................ 35 1.4 Hypothesis............................................................................................................... 36 1.5 Objectives and Relevance of Research ................................................................... 37 2. Materials and Methods .................................................................................................. 39 iv 2.1 Study Design, Patient Recruitment and Clinical Information ................................ 39 2.2 Study Families and Mode of Inheritance ................................................................ 43 2.3 Whole Exome Sequencing and Bioinformatics Analyses ...................................... 51 2.3.1 Library Preparation and Sequencing ................................................................ 51 2.3.2 Alignment and Quality Control Methods ........................................................ 52 2.3.3 Variant Calling and Annotation ....................................................................... 52 2.4 Filtering of Low, Moderate, and High Impact Variants ......................................... 56 2.4.1 Previously Identified Candidate Genes for IA ................................................. 56 2.4.2 Variant Filtering Strategy ................................................................................ 56 2.5 NextGene® Software ............................................................................................... 62 2.6 Additional Variant Prioritization ............................................................................ 64 2.7 Validation and Segregation Analyses ..................................................................... 65 2.8 Sanger Sequencing Protocol ................................................................................... 67 2.8.1 Polymerase Chain Reaction ............................................................................. 67 2.8.2 ExoSAP ............................................................................................................ 68 2.8.3 ABI Cycle Sequencing ..................................................................................... 69 2.9 Population Control Testing ..................................................................................... 70 3. Results ........................................................................................................................... 72 3.1 Variant Calls by MUGQIC ..................................................................................... 72 3.1.1 Data Summary Following Variant Calling ...................................................... 72 3.2 Initial Variant Filtering ........................................................................................... 73 3.2.1 Candidate Genes from Previous Studies .......................................................... 73 3.2.2 Data Summary Following Filtering of Whole Exome Variants ...................... 77 3.2.3 High Impact Variants: Family R1352 .............................................................. 79 3.2.4 Moderate Impact Variants: Family R1352 ...................................................... 79 3.2.5 Low Impact Variants: Family R1352 .............................................................. 81 3.2.6 High Impact Variants: Family R1256 .............................................................. 83 3.2.7 Moderate Impact Variants: Family R1256 ...................................................... 83 3.2.8 Low Impact Variants: Family R1256 .............................................................. 88 3.3 NextGene® Results ................................................................................................. 90 v 3.3.1 Family R1352 Variants .................................................................................... 90 3.3.2 Family R1352 Variants Shared by 4 Siblings .................................................. 91 3.3.3 Family R1256 Variants .................................................................................... 92 3.4 Homozygous Variation in Siblings from Family R1352 ........................................ 93 3.5 Validation and Segregation
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