Variable Clinical and Molecular Expressivity of PCDH19 Variants and Girls Clustering Epilepsy A disorder of cellular “mosaics” Thesis submitted for the degree of Doctor of Philosophy by Kristy Louise Kolc BSc-Psychology (Hons) April 2020 School of Population Health Faculty of Health Sciences The University of Adelaide, Australia University of Adelaide Adelaide Medical School, Faculty of HealthAustralia and Medical Sciences Children see magic because they look for it - Christopher Moore Science is nothing but perception. - Plato Title Variable Clinical and Molecular Expressivity of PCDH19 Variants and Girls Clustering Epilepsy: A disorder of cellular “mosaics” Author Kristy Kolc Institute Adelaide Medical School Academic advisors Professor Jozef Gecz, Adelaide Medical School A/Prof Rachel Roberts, School of Psychology Dr Duyen Pham, Adelaide Medical School Dr Raman Kumar, Adelaide Medical School Adelaide Medical School University of Adelaide Adelaide Health and Medical Sciences Building ADELAIDE SA 5000 E-mail: [email protected] webpage: https://health.adelaide.edu.au/medicine/ TABLE OF CONTENTS TABLE OF CONTENTS TABLE OF CONTENTS .............................................................................................................. i LIST OF TABLES ....................................................................................................................... v LIST OF FIGURES .................................................................................................................... vi LIST OF ABBREVIATIONS .................................................................................................... vii LIST OF CITATIONS ............................................................................................................... vii ABSTRACT ................................................................................................................................ xi THESIS DECLARATION ...................................................................................................... xivv ACKNOWLEDGEMENTS ....................................................................................................... xv Navigation & overview ............................................................................. 1 1.1 Navigation .............................................................................................................................. 2 1.2 Overview ................................................................................................................................ 2 A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity. ............................................................................................................ 5 2.1 Preamble................................................................................................................................. 6 2.2 Statement of authorship.......................................................................................................... 7 2.3 Published manuscript ........................................................................................................... 10 A standardized patient-centered characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy ........................................................ 26 3.1 Preamble............................................................................................................................... 27 3.2 Statement of authorship........................................................................................................ 28 3.3 Accepted manuscript ............................................................................................................ 32 Human Disease Genes Website Series – PCDH19 website ................. 47 4.1 Preamble............................................................................................................................... 48 4.2 Statement of authorship........................................................................................................ 49 4.3 Published website ................................................................................................................. 51 Levetiracetam efficacy in PCDH19 girls clustering epilepsy ............. 69 5.1 Preamble............................................................................................................................... 70 5.2 Statement of authorship........................................................................................................ 71 5.3 Published manuscript ........................................................................................................... 73 PCDH19 variants in males – Expanding the phenotypic spectrum ... 84 6.1 Preamble............................................................................................................................... 85 P a g e | i TABLE OF CONTENTS 6.2 Statement of authorship........................................................................................................ 86 6.3 Submitted manuscript .......................................................................................................... 88 Investigating cellular and gene expression determinants of variable penetrance in PCDH19 X-linked clustering epilepsy ............................................. 99 7.1 Preamble............................................................................................................................. 100 7.2 Statement of authorship...................................................................................................... 101 7.3 Prepared manuscript ........................................................................................................... 103 Discussion .............................................................................................. 117 8.1 Overview ............................................................................................................................ 118 8.2 Outcome 1: Predicting clinical outcomes........................................................................... 120 8.2.1 Earlier seizure onset age is significantly associated with more severe cognitive impairment ........................................................................................................................... 120 8.2.2 Earlier seizure onset age and more frequent seizures within a cluster are significantly associated with more severe ASD symptoms ...................................................................... 121 8.2.3 Clinical implications ................................................................................................... 121 8.3 Outcome 2: The neuropsychiatric profile of PCDH19 variants. ........................................ 121 8.3.1 The Social Responsiveness Scale, second edition and the Social Communication Questionnaire ....................................................................................................................... 122 8.3.2 Autism spectrum disorder ........................................................................................... 122 8.3.3 The Strengths and Difficulties Questionnaire ............................................................. 122 8.3.4 Attention-deficit hyperactivity disorder ...................................................................... 123 8.3.5 The Dimensional Obsessive-Compulsive Scale ......................................................... 123 8.3.6 Obsessive-compulsive disorder .................................................................................. 123 8.3.7 The Behavior Rating Inventory of Executive Function .............................................. 124 8.3.8 Executive functions .................................................................................................... 124 8.3.9 Clinical implications ................................................................................................... 124 8.4 Outcome 3: Treatment efficacy in Girls Clustering Epilepsy ............................................ 125 8.4.1 Levetiracetam ............................................................................................................. 125 8.4.2 Clinical implications ................................................................................................... 126 8.5 Outcome 4: Penetrance of PCDH19 pathogenic variants .................................................. 126 8.5.1 The cellular interference model .................................................................................. 126 8.5.2 Association between PCDH19 cDNA expression and clinical outcomes .................. 127 8.6 Strengths and limitations .................................................................................................... 128 8.7 Recommendations for further research .............................................................................. 129 8.8 Conclusions ........................................................................................................................ 131 P a g e | ii TABLE OF CONTENTS Appendix A: Survey assessments ........................................................................... 132 A1 Social Responsiveness Scale, second edition ..................................................................... 132 A2 Social Communication Questionnaire ...............................................................................