Variantes alélicas raras en la enfermedad de MénièreDe los casos familiares a los casos esporádicos

Résumé

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 main 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 MD in two novel families with MD phenotype and variable expressivity. Second goal is to understand genetics in many diagnosed MD cases around Spain and to find genetic markers associated to sporadic MD. As a previous step, we conducted a study to improve the bioinformatic protocol for candidate variants discovery by using multiple tools. The findings in this Thesis supports that: 1) Integration of multiple prediction and prioritization tools can be used as a protocol for discovery of candidate variants in exome datasets for families where few individuals are sequenced. 2) Validation of two novel candidate variants in SEMA3D and DPT in two families confirms genetic heterogeneity in familial MD with incomplete penetrance and variable expressivity. 3) The study of sporadic cases determined how some SNHL-related genes have an enrichment of missense variants in Spanish population. The candidate list includes well-known genes as GJB2, ESRRB, CLDN14, USH1G and SLC26A4.