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Rare Allelic Variants in Meniere's Disease from Familial to Sporadic

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Rare Allelic Variants in Meniere's Disease from Familial to Sporadic PROGRAMA DE DOCTORADO EN BIOMEDICINA (B11.56.1) RARE ALLELIC VARIANTS IN MENIERE’S DISEASE FROM FAMILIAL TO SPORADIC CASES VARIANTES ALÉLICAS RARAS EN LA ENFERMEDAD DE MENIERE DE LOS CASOS FAMILIARES A LOS CASOS ESPORÁDICOS INTERNATIONAL PhD THESIS TESIS DOCTORAL CON MENCIÓN INTERNACIONAL ALVARO GALLEGO MARTINEZ February 2019 GRANADA Editor: Universidad de Granada. Tesis Doctorales Autor: Álvaro Gallego Martínez ISBN: 978-84-1306-154-2 URI: http://hdl.handle.net/10481/55469 Index Contents Index .............................................................................................................................................. 1 Grants and funding ........................................................................................................................ 3 Abstract ......................................................................................................................................... 5 Resumen ........................................................................................................................................ 6 Abbreviations ................................................................................................................................ 7 Introduction ................................................................................................................................... 9 Anatomy of the inner ear ........................................................................................................ 11 2. Meniere’s Disease ........................................................................................................... 14 3. Epidemiology ................................................................................................................... 17 4. Pathophysiology .............................................................................................................. 18 5. Human genomics ............................................................................................................. 19 6. Variants ............................................................................................................................ 21 7. Next-generation sequencing technologies in HL and MD. .............................................. 27 8. Genetics ........................................................................................................................... 28 Hypothesis ................................................................................................................................... 31 Goals ............................................................................................................................................ 35 Methods ...................................................................................................................................... 39 1. Familial MD analysis ............................................................................................................ 41 1. Diagnosis of cases ............................................................................................................ 41 2. Familial samples .............................................................................................................. 41 3. Whole-exome sequencing (WES) .................................................................................... 42 4. Pipeline testing for candidate SNV priorization .............................................................. 42 5. Benchmarking procedures .............................................................................................. 45 6. Statistical analysis ............................................................................................................ 46 7. Bioinformatics tools for rare SNV selection .................................................................... 46 8. Control datasets to filter by Spanish population variants ............................................... 47 9. Minor allelic frequency filtering ...................................................................................... 47 10. Prioritization ................................................................................................................ 47 11. Linkage analysis ........................................................................................................... 47 12. Validation by Sanger Sequencing ................................................................................ 47 13. RNA extraction from cochlea and semicircular canals ................................................ 48 14. Expression analysis in tissue ........................................................................................ 49 15. Protein 3D modelling ................................................................................................... 49 16. Variant submission ...................................................................................................... 49 2. Sporadic MD analysis........................................................................................................... 50 1. Sporadic samples ............................................................................................................. 50 2. DNA extraction ................................................................................................................ 50 3. Selection of target genes ................................................................................................. 51 4. Preparation of pools ........................................................................................................ 51 5. Haloplex protocol (capture, enrichment, barcoding) ...................................................... 51 6. Data generation pipelines ............................................................................................... 52 7. Positive control SNV validation ....................................................................................... 53 8. Selection and priorization of pathogenic SNV ................................................................. 53 9. Validation of candidate pathogenic SNV ......................................................................... 54 10. Population statistics .................................................................................................... 54 11. Position of variants in significant enriched genes ....................................................... 55 Results ......................................................................................................................................... 59 1. Prioritizing variants in exome datasets ........................................................................... 59 2. Comparison of prioritizing strategies with FMD exome datasets ................................... 59 3. Benchmark in exome datasets containing variants described in AD-SNHL and CNM genes ....................................................................................................................................... 61 4. Families study .................................................................................................................. 64 5. Sporadic cases study ....................................................................................................... 71 6. Rare variants analysis ...................................................................................................... 75 7. Mitochondrial rare variants ............................................................................................. 78 8. Gene burden analysis ...................................................................................................... 82 Discussion .................................................................................................................................... 92 1. Candidate variant selection in singletons and small families .......................................... 92 2. Familial MD ...................................................................................................................... 94 3. Sporadic MD .................................................................................................................... 98 Conclusions ............................................................................................................................... 106 Bibliography ............................................................................................................................... 108 Supplementary data 2 Grants and funding Alvaro Gallego Martinez work and this thesis was feasible thanks to the following funds: Grant from ISCII PI13/01242 Grant from Meniere’s Society, UK Grant from Luxembourg National Research Fund INTER/Mobility/17/11772209 during three months in the Bioinformatics Core of the University of Luxembourg. 3 4 Abstract Meniere’s diseases [MD; MIM 156000] is a chronic disorder characterized by attacks of vertigo associated with sensorineural hearing loss (SNHL) involving low to medium frequencies. Although its etiology remains unknown, its prevalence is about 0.5 to 1 / 1000 individuals, affecting more to familial cases than sporadic cases. MD shows a high clinical heterogeneity and incomplete phenotypic forms that complicate its diagnosis. The goal of this thesis is to obtain a better and comprehensive image of the genetics surrounding MD disease and to characterise its sporadic and familial forms. Therefore, the first goal is to increase what we know about familial
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