The Clinical Characteristics of Families with Hypertrophic Cardiomyopathy Associated with Mutations of Cardiac Myosin Binding Protein C Thesis for the degree of MD(Res)

................................................................................................................................................. 4 INTRODUCTION: .......................................................................................................................................... 4 METHODS: .................................................................................................................................................. 4 RESULTS: .................................................................................................................................................... 4 DISCUSSION: ............................................................................................................................................... 5 TABLE OF CONTENTS ............................................................................................................................. 6 LIST OF TABLES ........................................................................................................................................ 8 LIST OF FIGURES .....................................................................................................................................10 ACKNOWLEDGEMENTS ........................................................................................................................12 INTRODUCTION .......................................................................................................................................14 PRE-AMBLE ...............................................................................................................................................15 OVERVIEW OF HYPERTROPHIC CARDIOMYOPATHY ...................................................................................16 Definition and Diagnosis .....................................................................................................................16 Epidemiology .......................................................................................................................................16 Pathology .............................................................................................................................................17 Aetiology and Pathogenesis .................................................................................................................18 Clinical Disease Expression ................................................................................................................19 Management .........................................................................................................................................23 Prognosis .............................................................................................................................................24 CARDIAC MYOSIN BINDING PROTEIN C ....................................................................................................28 The Spectrum of Clinical Disease in Patients with MYBPC3 Mutations .............................................31 A Historical Perspective ......................................................................................................................31 Prevalence of MYBPC3 Mutations in Patients with HCM ...................................................................32 Penetrance of Disease ..........................................................................................................................36 Age at Diagnosis in Patients with MYBPC3 Mutations .......................................................................39 Clinical Characteristics of Disease in Patients with MYBPC3 Mutations ..........................................40 Summary: .............................................................................................................................................44 METHODS AND SUBJECTS ....................................................................................................................46 AIMS AND OBJECTIVES ..............................................................................................................................47 METHODOLOGY .........................................................................................................................................47 Study Design ........................................................................................................................................47 Case Selection ......................................................................................................................................48 Clinical Evaluation ..............................................................................................................................49 Clinical Management ...........................................................................................................................52 Genetic Evaluation...............................................................................................................................53 DEFINITIONS ..............................................................................................................................................55 Statistics ...............................................................................................................................................56 ETHICAL APPROVAL AND FUNDING ...........................................................................................................57 THE SPECTRUM OF MYBPC3 MUTATIONS IN FAMILIES WITH HCM .....................................58 INTRODUCTION ..........................................................................................................................................59 METHODS ..................................................................................................................................................59 RESULTS ....................................................................................................................................................60 Index cases ...........................................................................................................................................60 Familial Mutation Analysis ..................................................................................................................63 DISCUSSION ...............................................................................................................................................64 DISEASE PENETRANCE, AGE AND GENDER IN FAMILIES WITH MYBPC3 MUTATIONS ..68