Application des stratégies combinées utilisant le séquençage d'exome dans les maladies vasculaires rares

Abstract : Identifying genes of Mendelian disorders has started within the eighties. The pace of new genes discovery has been dramatically accelerated by the availability of the human genome sequence in the 2000s, and the next-generation sequencing technologies in the 2010s. However, a majority of the elucidated conditions so far correspond to relatively simplified situations, where the prevalence and the penetrance of the condition are high and the genetic heterogeneity is low. Nowadays, geneticists meet more and more situations where gene identification in unknown disorders can be tricky. Heritable conditions that are very rare, heterogenous or with imperfect Mendelian transmission can only be elucidated using large cohorts of patients, with a very well-characterized phenotype. This requires clinical, financial and logistical efforts to be made by the research teams. Generally, using exome sequencing alone is not efficient enough to elucidate these types of conditions. The power of recently developed strategies comes from its association with other genetic analysis tools, that have been specifically developed in the context of rare, heterogenous, or polygenic disorders. I employed exome sequencing in the identification of cardiovascular genetic conditions, using three different strategies. In the first condition, called hereditary xerocytosis, using linkage analysis together with exome sequencing of distant relatives was successful in identifying the causative gene. This was made possible by the identification of a reliable endophenotype, and the relative genetic homogeneity of the disorder. The second condition I studied is the abdominal aortic aneurysm (AAA), a common disorder with a strong hereditary component and rare situations of fully penetrant, dominant inheritance. I combined exome sequencing in a family with dominant inheritance with rare variants analysis of the candidate gene in a large cohort of sporadic AAA. This analysis is more complex and can be hazardous in the context of a candidate gene approach. The third strategy was developed for the study of fibromuscular dysplasia (FMD) which is a very heterogenous condition with low penetrance and no specific endophenotype. I combined exome sequencing in a group of 30 cases and relatives with filtering strategies for any type of Mendelian inheritance. I also used available bioinformatics tools and databases for refining the candidate genes filtering. This strategy provided promising results, probably due to the genetic characteristics of this condition. In each of these examples, I adapted the analysis strategy to the peculiarities of the disorder. The results presented here enable to evaluate the efficiency of combined approaches using exome sequencing. Their specificities, limits, and the optimization that need to be done to elucidate the remaining unsolved genetic conditions are discussed.
Keywords : Genetic
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Juliette Albuisson. Application des stratégies combinées utilisant le séquençage d'exome dans les maladies vasculaires rares. Médecine humaine et pathologie. Université Sorbonne Paris Cité, 2015. Français. ⟨NNT : 2015USPCB119⟩. ⟨tel-01541588⟩

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