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Marfan Syndrome Diagnostics, Epidemiology, and Aortic Events

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Marfan Syndrome Diagnostics, Epidemiology, and Aortic Events Marfan syndrome Diagnostics, epidemiology, and aortic events PhD dissertation Kristian Ketill Ambjørn Groth Health Aarhus University 2016 2 Marfan syndrome Diagnostics, epidemiology, and aortic events PhD dissertation Kristian Ketill Ambjørn Groth Health Aarhus University Department of Cardiology Department of Molecular Medicine Department of Endocrinology and Internal Medicine Department of Clinical Medicine 3 Supervisors Professor Claus H. Gravholt, Ph.d, dr.med. Department of Molecular Medicine (MOMA), Aarhus University Hospital, SKS Department of Endocrinology MEA, Aarhus University Hospital, NBG Niels Holmark Andersen, Ph d, dr.med. Department of Cardiology, Aarhus University Hospital, SKS Professor John Østergaard, dr.med. Center for Rare Diseases, Department of Pediatrics, Aarhus University Hospital, SKS Opponents Svend Rand-Hendriksen, Ph.d TRS, Sunnaas sykehus, 1450 Nesoddtangen Associate Professor Jacob Tfelt-Hansen, Ph.d Department of Cardiology, Rigshospitalet Clinical Associate Professor Kent Lodberg Christensen, Ph.d, dr. med. Department of Cardiology, Aarhus University Hospital 4 The thesis is based on the following manuscripts: 1. Difficulties in diagnosing Marfan Syndrome relying on existing FBN1 databases. Kristian A Groth, Mette Gaustadnes, Kasper Thorsen, John R. Østergaard, Uffe Birk Jensen, Claus H. Gravholt, Niels H. Andersen. Genet Med. 2016 Jan;18(1):98-102. 2. Evaluating Marfan genotype-phenotype correlations in existing FBN1 databases. Kristian A Groth, Yskert Von Kodolitsch, Kerstin Kutsche, Mette Gaustadnes, Kasper Thorsen, Niels H. Andersen, Claus H. Gravholt Accepted for publication in Genetics in Medicine. 3. Prevalence, incidence, and age at diagnosis in Marfan Syndrome. Kristian A Groth, Hanne Hove, Kasper Kyhl, Lars Folkestad, Mette Gaustadnes, Niels Vejlstrup, Kirstine Stochholm, John R. Østergaard, Niels H. Andersen, Claus H. Gravholt Orphanet J Rare Dis. 2015 Dec 2;10:153. 4. Aortic events in a nationwide Marfan Syndrome cohort Kristian A Groth, Kirstine Stochholm, Hanne Hove, Kasper Kyhl, Pernille Axelsen Gregersen, Niels Vejlstrup, John R. Østergaard, Claus H. Gravholt, Niels H. Andersen Clin Res Cardiol. 2016 Aug 22. [Epub ahead of print] 5 Preface The work in this thesis is done in cooperation between the Department of Cardiology and the Department of Molecular Medicine at Aarhus University Hospital, Aarhus Denmark. The studies were carried out during my PhD fellowship in the period 1st of May 2013 to 30th of April 2016. 6 Acknowledgements I owe a special and deep-felt gratitude to my closest supervisors Niels Holmark Andersen, prof. Claus Højbjerg Gravholt and prof. John Østergaard for unique guidance, inspiration and motivation. I am grateful to have benefitted from their support both academically and personally. I could not have asked for better supervisors. During the last three years I have been in contact and cooperated with so many helpful and inspiring people who I all owe gratitude. Special thanks go to Prof Torben Falck Ørentoft, Mie Gade Farsinsen and Connie Juhler and the rest of Department of Molecular Medicine (MOMA) for providing the vital physical and academic condition in which I have done my research. The people at MOMA have given me new knowledge on genetics and I have learned the basis of variant analysis. For this I owe a special thanks to the analyst group on the “second floor” Mette Gaustadnes, Friedrik Wikman and Lisbeth Nørum Pedersen. Also the “NGS people” on the 4th floor have been helpful in enlightening me in the area of sequencing DNA. Special thanks go to Kasper Thorsen for his always happy mind and inspiring cooperation. Katja Adolf is the sole reason that I did not experience computer failures and she have been very helpful in providing support in computer and software issues as well as suggestions on database handling. At the Department of Cardiology I owe a special gratitude to Mie Bruun who provided a unique help in handling everything from patients records to blood samples. Whenever Mie is involved things just work! Also the nurses at the GUCH outpatient clinic have been helpful when consulting Marfan syndrome patients. Thanks to Helena Friis Jensen, Tina Isager, Hanne Kildahl Mathiasen, and Connie Willer Albertsen for having me around. Center for Rare diseases have been most welcoming and especially the Marfan conferences have been highly interesting and I have learned a lot about Marfan syndrome from Stense Farholt and Pernille Axel Gregersen. 7 I have a special connection to Department of Endocrinology and Internal Medicine (MEA) established by Claus. I owe Sine Knorr, Anne Skakkebæk, Agnethe Berglund, Christian Høst, Anders Bojesen and the rest of the research group around Claus great appreciation. Very special thanks go to Kirstine Stochholm who has provided a very special and skilled statistical effort in my work and Kirstine “you are my statistical guru”. I appreciate the close cooperation I have with Department of Clinical Genetics and especially Prof. Uffe Birk by whom I have gained important genetic knowledge. I owe thanks to Marianne Geilswijk and Maria Rasmussen for their interesting cooperation. I also owe gratitude to national partners. At Rigshospitalet, my gratitude goes to Department of Cardiology especially Niels Vejlstrup and Kasper Kyhl, and the Department of Pediatrics’ Center for rare diseases with a special gratitude to Hanne Hove. Also the employees at the hospital archive placed a TV-byen in Søborg have provided vital support and I owe a special thanks to head of the archive Bjarne Rødtjer. At Odense University Hospital, Department of Cardiology Jens Mogensen has been highly inspiring as an expert in cardiology and genetics. I also owe gratitude to prof. Ulrik T. Baandrup for coorporation and kind hospitality in Hjørring and I owe a speciel gratitude to Ulrik for a quick response in providing microscopic pictures of cystic media necrosis. Without the support in providing access to patient files from other hospitals and departments around the country this thesis would not have been possible. I owe thanks to Odense University Hospital, Sydvestjysk Sygehus, Aalborg University Hospital, Regionshospital Herning, and Regionshospital Randers. To my international collaborators in Germany I owe a special gratitude to Yskert Von Kodolitsch, Kerstin Kutsche. I also owe my wife, friends and family great gratitude for invaluable support during the last three years of my Ph.d work. 8 Table of contents Preface 6 Acknowledgements 7 Table of contents 9 List of abbreviations and explanations 11 Introduction 13 Diagnosing Marfan syndrome 13 The need for an FBN1 gene test when diagnosing Marfan syndrome 20 The FBN1 gene and MFS 20 Analysing FBN1 variants 21 Variant databases 24 MFS prevalence 25 Mortality in MFS 25 Systemic disease MFS 26 Aortic events in MFS 26 Aim of the thesis 28 Methods 29 Background study 1 29 Methods study 1 29 Methods study 2 30 Methods study 3 and study 4 33 Statistical analysis 35 Results 36 Study 1 - Evaluation of 23 common variants 36 FBN1 database (study 2) 40 Forming the Danish MFS cohort 43 Prevalence and incidence 44 Aortic events (study 4) 48 Discussion 54 Evaluating the MFS diagnosis 54 Evaluating FBN1 variants for causality 54 Establishing a curated FBN1 database and the Marfan-score as a new tool in analyzing FBN1 variants 56 Creating a Marfan cohort 58 Prevalence of MFS 59 9 Incidence 61 Age at diagnosis 62 Aortic events in MFS 63 Gender difference in MFS 64 MFS patient follow-up and a MFS database 65 Conclusions 67 Perspectives 68 Summaries 69 Resumé 71 List of references 73 Supplemental material 89 Appendix 109 10 List of abbreviations and explanations ACMG The American College of Medical Genetics and Genomics. Berlin criteria A list of phenotypical features distinctive for a set of connective tissue conditions including Marfan syndrome. The criteria was published in 1988 and included a set of major manifestation and a demand of affection of more than one organ system1. CI Confidence Interval of 95% ClinVar Variant database based on an initiative of the National Center for Biotechnology Information (NCBI). CPR-number A personal identification number for Danish citizens. The number is registered in the Central Personal register. The CPR number can be used for record linkage across Danish registries. Database-MFS Variants reported to be associated with Marfan syndrome by one of the FBN1 databases. DNPR Danish National Patient Registry. DRCD Danish Register of Cause of Death. DST Statistical Denmark (www.dst.dk) E-journal A Danish electronic patient record system gathering patients record from Danish hospitals in one system. ESP NHLBI GO Exome Sequencing Project driven by the National Heart, Lung, and Blood Institute (NHLBI) ESP6500 A version of the ESP containing data on around 6500 exomes. FBN1 Gene coding for the protein Fibrillin-1. Ghent I criteria A revision of the Berlin criteria but still the first set of diagnostic criteria with a sole focus on Marfan syndrome. The criterion was published in 1996. The criteria came short after the discovery of variants in the FBN1 gene as causal for the condition.2 The criteria include major and minor criteria as well as affection of more than organ system. Ghent II criteria A revision of the Ghent I criteria abandoning the major and minor criteria but introducing a new systemic point scoring system. The criteria highlight aorta dilatation and FBN1 variants. The Ghent II criteria is somehow easier to use by the clinician as unspecific phenotypical criteria was abandoned. HGDM Human Gene Mutation Database. A general variant database also including the FBN1 gene. HR Hazard Ratio ICD International Classification of Disease. In this thesis is used references to the version 8 (ICD-8) and version 10 (ICD-10). 11 Marfan-score A score based on the Ghent II systemic scoring system and aorta dilatation to stratify phenotype in associations with FBN1 variants. MFS Marfan syndrome NCBI National Center for Biotechnology Information. NGS Next Generation Sequencing. Non-database-MFS Variant reported in at least one FBN1 database but none of the databases associated the variant to Marfan syndrome.
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