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Exome Sequencing in Hereditary Fakultät für Medizin Technische Universität München EXOME SEQUENCING IN HEREDITARY NEPHROPATHIES Korbinian Maria Riedhammer Vollständiger Abdruck der von der Fakultät für Medizin der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Medizin (Dr. med.) genehmigten Dissertation. Vorsitzender: Prof. Dr. Jürgen Schlegel Prüfende der Dissertation: 1. Priv.-Doz. Dr. Julia Höfele 2. Prof. Dr. Clemens Cohen 3. apl. Prof. Dr. Lutz Renders Die Dissertation wurde am 03.08.2020 bei der Technischen Universität München eingereicht und durch die Fakultät für Medizin am 16.02.2021 angenommen. In Gedenken an meinen Vater, Dr. med. Hans Harald Riedhammer. Everything is going to be fine in the end. If it's not fine it's not the end. Oscar Wilde ABSTRACT Introduction: Hereditary kidney diseases affect about one in ten adults with chronic kidney disease (CKD) and about two-thirds of patients with CKD-onset under the age of 25 years. Hence, they pose a considerable burden of disease. All parts of the intricate organ that is the kidney and urinary tract can be altered and hereditary nephropathies are therefore clinically and genetically vastly heterogeneous. Exome sequencing (ES), that is, the analysis of the protein-coding regions of the human genome, is able to address this genetic heterogeneity. Aim of this thesis: Evaluation of ES in 260 index cases with a clinically presumed hereditary nephropathy with emphasis on the detection of phenocopies (clinical tentative diagnosis is different from genetic diagnosis), the prioritization of novel disease-associated genes (“candidate genes”), and the statistical analysis of the cohort to improve clinical decision-making. Study design: Cross-sectional study. Methods: ES in 260 genetically unsolved index cases recruited between October 2015 and February 2019. Results: 77 of 260 cases could be genetically solved (a diagnostic yield of 30%). In 12 of 77 solved cases (16%), a phenocopy was identified. In 8 of 260 cases (3%), a candidate gene could be prioritized. There were significant differences in Alport syndrome (AS) versus thin basement membrane nephropathy (TBMN), the two poles of disease severity of type-IV-collagen-related nephropathy: Diagnostic yield was significantly higher in AS than in TBMN (65% vs. 28%, p = 0.01). Median age at first manifestation was significantly lower in AS than in TBMN (5.5 years [3.0–9.0] vs. 16.0 years [5.0–32.3], p = 0.001). There were no extrarenal manifestations in TBMN cases, compared to 28% in AS cases (p = 0.01). A family history was less commonly reported in TBMN cases than in AS cases (39% vs. 78%, p = 0.006). For the total cohort, clinical predictors of a solved case were positive family history (odds ratio [OR] 6.61 [95% confidence interval 3.28–13.35], p < 0.001), an extrarenal manifestation (OR 3.21 [1.58–6.54], p = 0.01) and – with a borderline significance – younger age at first manifestation (OR 0.97 [0.93–1.00], p = 0.048). Discussion: This thesis shows the utility of ES in hereditary nephropathies by the identification of phenocopies, which have major implications for disease management and prognosis, and of novel disease- associated genes. Furthermore, the results of this thesis guide the genetic work-up of patients by presenting statistical evidence for predictors of a positive genetic result and for delineating the disease spectrum of type-IV-collagen-related nephropathy. ACKNOWLEDGMENTS I would like to thank my doctoral supervisor, PD Dr. Julia Hoefele, for her excellent support. Additionally, many thanks to Univ.-Prof. Dr. Thomas Meitinger, the head of the Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany, for filling me with enthusiasm for the field of human genetics. My family has been a beacon of support – my mother, Margit Riedhammer; my sister, Anna-Katharina Hiemer; my brother-in-law, Daniel Hiemer; and my girlfriend, Johanna Greiner. All my love to them: I would not have completed this thesis without them. I would further like to thank the medical technical assistants at the Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany, and at the Institute of Human Genetics and the Next-Generation Sequencing Core Facility at the Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany. Further thanks to Dr. Matthias Braunisch, Dr. Bettina Lorenz-Depiereux, and Dr. Matias Wagner for proofreading of the manuscript. Thank you to Kayla Friedman and Malcolm Morgan of the Centre for Sustainable Development, University of Cambridge, United Kingdom, for producing the Microsoft Word thesis template used to produce this document. Finally, I thank all referring clinicians and collaboration partners and, last but not least, the index patients and their legal guardians for participating in this study. 5 TABLE OF CONTENTS GLOSSARY ..................................................................................................................... 9 LIST OF ABBREVIATIONS AND ACRONYMS .................................................................... 18 ONLINE RESOURCES ..................................................................................................... 23 1 INTRODUCTION ...................................................................................................... 25 1.1 HEREDITARY NEPHROPATHIES ................................................................................ 26 1.1.1 Autosomal dominant tubulointerstitial kidney disease (ADTKD) ................ 27 1.1.2 Alport syndrome (AS) .................................................................................... 31 1.1.3 Congenital anomalies of the kidney and urinary tract (CAKUT) .................. 35 1.1.4 Ciliopathies .................................................................................................... 40 1.1.5 Hereditary focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome (FSGS/SRNS) ......................................................................................... 47 1.1.6 VACTERL/VATER association .................................................................... 54 1.1.7 Other hereditary nephropathies ...................................................................... 54 1.1.7.1 Tubulopathies .................................................................................................................................... 54 1.1.7.2 Inherited metabolic disorders ............................................................................................................ 55 1.1.7.3 Mitochondrial disorders .................................................................................................................... 56 1.1.7.4 Atypical hemolytic uremic syndrome (complement-mediated hemolytic uremic syndrome) ........... 56 1.2 EXOME SEQUENCING .............................................................................................. 58 1.2.1 Exome sequencing in general, its utility and limitations ............................... 58 1.2.2 Exome sequencing in hereditary nephropathies ............................................. 63 1.2.3 Comprehensive genetic testing for the detection of phenocopies in hereditary nephropathies .......................................................................................................... 66 1.3 GENOMICS IN HEREDITARY NEPHROPATHIES – OUTLOOK ....................................... 67 1.4 GENETICS OF NON-MONOGENIC KIDNEY DISEASES ................................................. 67 2 AIM OF THIS THESIS ............................................................................................. 70 3 PATIENT COHORT, MATERIAL, AND METHODS ......................................... 71 3.1 PATIENT COHORT ................................................................................................... 71 3.1.1 Patient recruitment and consent ..................................................................... 71 3.1.2 Phenotype ascertainment ................................................................................ 73 3.2 SAMPLE PROCESSING, POLYMERASE CHAIN REACTION, AND SANGER SEQUENCING 77 3.2.1 DNA isolation ................................................................................................ 77 6 3.2.1.1 Manual DNA isolation ...................................................................................................................... 77 3.2.1.2 Automated DNA isolation ................................................................................................................ 78 3.2.2 DNA quantification and quality check ........................................................... 78 3.2.3 Polymerase chain reaction ............................................................................. 79 3.2.3.1 Basic method ..................................................................................................................................... 79 3.2.3.2 Materials and procedure .................................................................................................................... 79 3.2.3.3 Agarose gel electrophoresis .............................................................................................................. 80 3.2.3.4 PCR purification ............................................................................................................................... 81 3.2.4 Sanger sequencing .........................................................................................
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