Análisis agregado de variantes en el exoma de pacientes con enfermedad de Meniere familiar e inicio precoz

Résumé

Introduction: Meniere’s disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo and tinnitus. Although most of MD patients are sporadic, familial aggregation is observed in 6-9% of these patients, suggesting a genetic contribution in MD. MD is a complex disease, showing phenotypic heterogeneity as well as genetic heterogeneity. To date, only variants in single families have been associated to familial MD, finding no replication in non-related families. Objectives: To identify the main genes involved in familial MD by whole exome sequencing, and to demonstrate an aggregate effect of variants in certain genes. Furthermore, the main biological processes and pathways will be analyzed, and the results will be compared with sporadic MD patients. Methods: A total of 138 MD patients (94 familial MD patients and 44 sporadic MD patients) diagnosed according to the criteria defined by the Barany Society were recruited and sequenced to look for rare variants. Minor allelic frequencies of identified variants were annotated to undertake a single rare variant and a gene burden analyses. Allelic frequencies were compared with the frequencies from European and Spanish reference datasets. Over-representation analyses were done to identify the main biological processes and pathways. Results: In a first approach of the genetic MD background, we identified that 40% of familial MD patients and 68% of sporadic MD patients carried, at least, a novel or ultrarare variant in a gene linked to sensorineural hearing loss. Analyzing these genes, enrichment of rare variants were identified in some of them, standing out the gene which encodes otogelin, OTOG. Ten variants were found in 15 nonrelated families. Studying the clinical information of these patients, an endophenotype characterized by flat hearing loss with no progression was observed. Finally, we analyzed all the genes within the human genome. The results obtained from this analysis suggest a polygenic and/or a polyallelic contributions in MD, being different the genes involved in familial and sporadic MD. Based on these results, pathways such as axon guidance were identified throughout an over-representation analysis as key pathways in MD. Conclusions: In this doctorate thesis, the main potential genes and pathways for familial MD have been defined, finding a differential genetic background between sporadic and familial MD. These results could be the basis for future genetic and functional studies on MD.