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Novel Gene Discovery in Primary Ciliary Dyskinesia

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Novel Gene Discovery in Primary Ciliary Dyskinesia Novel Gene Discovery in Primary Ciliary Dyskinesia Mahmoud Raafat Fassad Genetics and Genomic Medicine Programme Great Ormond Street Institute of Child Health University College London A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy University College London 1 Declaration I, Mahmoud Raafat Fassad, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Primary Ciliary Dyskinesia (PCD) is one of the ‘ciliopathies’, genetic disorders affecting either cilia structure or function. PCD is a rare recessive disease caused by defective motile cilia. Affected individuals manifest with neonatal respiratory distress, chronic wet cough, upper respiratory tract problems, progressive lung disease resulting in bronchiectasis, laterality problems including heart defects and adult infertility. Early diagnosis and management are essential for better respiratory disease prognosis. PCD is a highly genetically heterogeneous disorder with causal mutations identified in 36 genes that account for the disease in about 70% of PCD cases, suggesting that additional genes remain to be discovered. Targeted next generation sequencing was used for genetic screening of a cohort of patients with confirmed or suggestive PCD diagnosis. The use of multi-gene panel sequencing yielded a high diagnostic output (> 70%) with mutations identified in known PCD genes. Over half of these mutations were novel alleles, expanding the mutation spectrum in PCD genes. The inclusion of patients from various ethnic backgrounds revealed a striking impact of ethnicity on the composition of disease alleles uncovering a significant genetic stratification of PCD in different populations. Pathogenic mutations were also identified in several new candidate genes not previously linked to PCD. Molecular and cell biology techniques were coupled with model organism studies to characterize the involvement of the new candidate genes in cilia motility and PCD. Paramecium was proven to be a good model for functional characterization of PCD potential candidate genes. The previously uncharacterized C11orf70 was identified to play a highly conserved role in dynein assembly and intraflagellar transport (IFT)-related cilia cargo trafficking. Mutations identified in DNAH9 resulted in a distinct motile cilia defect with mild respiratory symptoms, unusual in PCD. Mutations identified in two intraflagellar transport genes, IFT74 and WDR19, linked together primary and motile ciliopathy phenotypes observed in the affected individuals. 3 Impact Statement Motile cilia are continuously beating hair-like structures that clear airways, move gametes and determine left-right organ position. Defective cilia motility in primary ciliary dyskinesia (PCD) causes chronic respiratory problems and lung damage, infertility, hydrocephalus, malpositioned organs and heart defects. No single test currently confirms or excludes the diagnosis of PCD, a disease for which there is no cure. Working towards better PCD diagnosis and molecular understanding for improved disease management and development of personalized genetic therapies, this study used advanced sequencing techniques for genetic screening of PCD patients to aid novel gene discovery. This study isolated several new genes not previously linked to PCD, providing fresh insights into: its cell biological basis by describing a new X- linked PCD subtype and a new player in dynein assembly (PIH1D3, C11orf70); genetic contribution to poorly recognised mild-spectrum subtypes of PCD (DNAH9, CCDC103); causes of respiratory incapacity within primary ciliopathies (IFT74, WDR19). By expanding the genetic landscape of PCD, we can improve genetic diagnosis. Genetic testing avoids the disadvantages and inconclusive results of other diagnostic testing methods currently used in healthcare, and consequently it will expedite the diagnostic pathway of PCD and facilitate better characterization of patients. Upon identification of the whole morbid genome of PCD, genetic testing can be considered a first-tier PCD diagnostic test. Genetic results from this study have already contributed to two larger studies. Firstly, a published investigation of risk factors for laterality abnormalities and congenital heart defects in PCD, many being clinically actionable. This led to a recommendation for routine echocardiogram and abdominal ultrasound for all PCD patients. Secondly, a nationwide study, to be submitted shortly, to understand PCD genotype/phenotype correlations in the UK. These efforts will eventually help clinical management and inclusion in future therapeutic trials. 4 Patients from various ethnic backgrounds were recruited for this study, demonstrating successful international collaborations and the valuable outputs gained from multi-ethnic genetic studies in rare diseases. This will help in better genetic stratification of rare diseases, paving the way for future targeted therapy. This type of study can help countries with limited resources to pursue tailored testing strategies for genetic diagnosis of rare diseases. Moreover, this will help to provide appropriate genetic counselling to affected families. Two successful training placements were undertaken in different laboratories abroad, building new multi-disciplinary collaborations across Europe in motile cilia research. Introducing Paramecium as a new model organism in PCD will help to identify new disease genes and validate the role of potential candidate genes in cilia motility. Bringing new proteomics skills to the UCL laboratory adds new prospects to the study of PCD disease mechanisms and how gene mutations cause disease phenotypes. Understanding the molecular basis of human diseases is an essential step to investigate future personalized therapeutic strategies. Identifying motile cilia defects associated with primary ciliopathy phenotypes highlights the importance of investigating respiratory problems in ciliopathy syndromes. This can help in the management of the affected individuals, especially as respiratory failure is a common cause of death among these patients. 5 Acknowledgements First and foremost, I feel indebted to Allah the most merciful and most compassionate who enabled me to accomplish this work I would like to express my greatest gratitude to Dr Hannah Mitchison for her meticulous supervision and true concern to accomplish this work in the best possible image. My gratitude extends to Prof Stephen Hart and Dr Eddie Chung for their precious scientific guidance and continuous support. This PhD would not have been possible without the immense help and valuable support from all my colleagues within Cilia Disorders Section. Special thanks go to my office and lab mate; Mitali Patel and my colleague and sister; Dr Rasha Nour. I would like to extend my thanks to all members of the UK PCD diagnostic and management service especially Dr Amelia Shoemark and my collaborators in Egypt, Palestine and Portugal. I am also grateful to Dr Anne-Marie Tassin and Dr Karsten Boldt for hosting me in their labs and providing unlimited help and constructive guidance. Words are not enough to express my deepest thanks and endless gratitude to my parents, my brother; Mohamed, my sisters; Shimaa and Asmaa, my fiancée; Salsabil and all my friends for their endless support and continuous encouragement throughout my whole life. My appreciation and thanks to my cousin; Ahmed, his wife; Jennifer and their lovely daughter; Rou’aia for opening their house to me to stay with them over the past three years. I would like to thank the British Council and the Egyptian government through the Ministry of Higher Education for giving me this opportunity to pursue PhD studies at University College London through Newton-Mosharafa Fund. Last but not least, I would like to express my deepest thanks to all patients and their families for their kind cooperation. 6 Table of Contents DECLARATION....................................................................................................... 2 ABSTRACT ………………………………………………………………………………..3 IMPACT STATEMENT ............................................................................................ 4 ACKNOWLEDGEMENTS ....................................................................................... 6 TABLE OF CONTENTS .......................................................................................... 7 LIST OF FIGURES ................................................................................................ 10 LIST OF TABLES .................................................................................................. 14 LIST OF ABBREVIATIONS................................................................................... 15 PUBLICATIONS FROM THIS THESIS .................................................................. 19 PUBLISHED ABSTRACTS ................................................................................... 21 CHAPTER 1 INTRODUCTION .............................................................................. 22 1.1 CILIA STRUCTURE ...................................................................................... 23 1.2 NON-MOTILE AND MOTILE CILIA IN HEALTH AND DISEASE ............................... 26 1.3 PRIMARY CILIARY DYSKINESIA ................................................................... 29 1.3.1 History of PCD .................................................................................
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