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Autosomal Recessive Variants in Intellectual Disability and Autism Spectrum Disorder

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Autosomal Recessive Variants in Intellectual Disability and Autism Spectrum Disorder Autosomal Recessive Variants in Intellectual Disability and Autism Spectrum Disorder by Ricardo Simeon Harripaul A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy of Medical Science Institute of Medical Sciences University of Toronto © Copyright by Ricardo Simeon Harripaul 2021 Autosomal Recessive Variants in Intellectual Disability and Autism Spectrum Disorder Ricardo Simeon Harripaul Doctor of Philosophy of Medical Science Institute of Medical Sciences University of Toronto 2021 Abstract The development of the nervous system is a tightly timed and controlled process where aberrant development may lead to neurodevelopmental disorders. Two of the most common forms of neurodevelopmental disorders are Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). These two disorders are intertwined, but much about the etiological relationship between them remains a mystery. Little attention has been given to the role recessive variants play in ID and ASD, perhaps related to the ability of recessive variants to remain hidden in the population. This thesis aims to help determine the role of recessive variants in ID and ASD and identify novel genes associated with these neurodevelopmental disorders. Technological advancements such as Next Generation Sequencing (NGS) and large population-scale sequencing reference sets have ushered in a new era of high throughput gene identification. In total, 307 families were whole-exome sequenced (192 consanguineous multiplex ID families and 115 consanguineous trio ASD families), representing 537 samples in total. This work identified 26 novel genes for ID such as ABI2, MAPK8, MBOAT7, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44 in large multiplex families with an overall diagnostic yield of 51 %. ASD often has other comorbid features and the connection with ID and ASD has been observed in literature with an estimated 40-70% if ASD probands also have comorbid ID. Extending the use of consanguineous families in autosomal recessive variant identification in ASD, the diagnostic yield for this ASD trio cohort was ~26 %, with 28 of the known variants coming from previously ii known genes. This study identified putative variants with functional mouse models that display behavioral and nervous system abnormalities involving genes such as EPHB1, VPS16, CNGA2 and EFR3B. Of the neurodevelopmental genes from this cohort, ZNF292 is the most associated with ID with or without syndromic features and ASD. The overall body of work highlights the clinical and genetic heterogeneity in neurodevelopmental disorders and demonstrates the important role that recessive variants have in neurodevelopment disorders, including ASD. The identification of novel genes will hopefully provide better diagnosis and clinical management for patients. iii Acknowledgments I would like to thanks my supervisor Dr. John Vincent for his mentorship and guidance throughout my PhD. Thank you for giving me the opportunity and the freedom to explore and learn. To my Program Advisory Committee Dr. Lisa Strug, Dr. Phillip Awadalla, Dr. Leon French, and Dr. Joyce So for their perspectives, feedback, support and insights to improve my experimental design and myself. I would also like to thank Drs. Muhammad Ayub and Bita Bozorgmehr for their clinical insight and patient recruitment. I thank Dr. Arun Tiwari and Dr. Clement Zai for their help, honesty, listening and friendly discussion. I would like to thank the MiND Lab and the lab members. Thank you, Anna Mikhailov, for managing the lab and making research easier for everyone. You were always quiet and patient. I also thank all the lab members Dr. Taimoor Sheikh, Stephen Pastore, Rebecca Lau, Farah Machcher and Dr. Nasim Vasli. Thank you to Fleming College for the great group of students that came to our lab Samantha, Manisha, Kayla and Ashlyn, Kamalben, Lauren, Shemika and Jenelle. Gene validation would not be possible without their hard work. Thank you to Andy Wang and David Rotenberg of Krembil Centre for Neuroinformatics, for allowing me to use the cluster to progress my research as I did. They truly enable science at CAMH. I would like to thank the funding support of the Canadian Institute of Health Research and the University of Toronto, Ontario Student Opportunity Trust Funds, Peterborough K.M. Hunter Charitable Foundation Graduate Awards for their financial support. I would like to thank my friends Sejal, Kayla, Kap and Akhil for their support and encouragement. I would like to thank my parents Wayne and Tara Harripaul for their continual support and strength in this long journey. My sister Anastasia Harripaul-Yhap for support and listening. I would also like to thank Emily for her editing and patience with me. I would also like to thank the families and patients that participated in these students as the research findings would not be possible without them. iv Contributions The content presented in this thesis is original work and the majority of the work, including study design, data analysis and manuscript preparation was done by the author Ricardo Harripaul. Below are the individuals who have contributed to the work presented in this thesis. Dr. John Vincent (Supervisor) for guidance in the mentorship in the study design, interpretation of results and manuscript preparation. Dr. Ghayda Mirzaa (collaborator) for her clinical insights into ZNF292 and the spectrum of clinical features in this specific gene. Dr. Muhammad Ayub (collaborator) for his patient recruitment, clinical insights and aid in manuscript preparation and result interpretation. Dr. Leon French (collaborator and Program Advisory Committee Member) for his mentorship and guidance in gene expression and neuroimaging analysis. v Table of Contents Table of Contents ........................................................................................................................... vi List of Tables ................................................................................................................................. xi List of Figures .............................................................................................................................. xiii List of Appendices ..................................................................................................................... xviii List of Abbreviations .....................................................................................................................xx Introduction: Dissecting the Genetic Causes of Intellectual Disability by Genetic Sequencing ..................................................................................................................................1 Pre-NGS High-throughput Sequencing Research for Gene Identification ..........................2 X Chromosome –Targeted Sequencing Studies ..................................................................3 Targeted Sequencing Studies ...............................................................................................4 Whole-Exome Sequencing for Gene Identification .............................................................5 Whole Genome Sequencing for Gene Identification ...........................................................7 Structural Variant Detection through NGS for Gene Identification in Intellectual Disability ..............................................................................................................................9 NGS Strategies for Clinical Diagnostics............................................................................10 Aims and Hypothesis .........................................................................................................11 1.8.1 Study One - Autosomal recessive variants in intellectual disability in consanguineous populations ..................................................................................11 1.8.2 Study Two – Whole exome sequence analysis in autism spectrum disorder trios from consanguineous populations .................................................................12 1.8.3 Study Three – De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder .............12 Autosomal Recessive Variants in Intellectual Disability in Consanguineous Populations ......14 Abstract ..............................................................................................................................15 Introduction ........................................................................................................................15 Materials and Methods .......................................................................................................17 vi 2.3.1 Family recruitment .................................................................................................17 2.3.2 Autozygosity mapping ...........................................................................................19 2.3.3 Structural Variant Analysis using Microarray .......................................................20 2.3.4 Whole exome sequencing ......................................................................................21 2.3.5 Sequencing alignment and variant calling .............................................................21 2.3.6 Variant Filtration ....................................................................................................22 2.3.7 Gene list construction ............................................................................................22
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