L'approche basée sur le génotype déterminé par séquençage haut-débit en première intention et le partage international des données pour identifier de nouveaux gènes et nouveaux syndromes responsables d'anomalies du développement

Abstract : Developmental disorders (DD) include malformative disorders and neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). These clinical features can be isolated or combined in a given patient, they affect around 3% of worldwide population. These disorders are responsible for major morbidity and mortality, for hospitalization especially in pediatric departments, for disabilities and, therefore, this represents a public health priority. Since 2004, in France, several national plans were conducted and extended, the last one being the 3rd National Plan for Rare Disorders (PNMR 2018-2022) which include 10 main goals, among others increasing diagnosis yield, decrease diagnosis wandering, increasing access to innovation and boost research.Diagnosis yield in patients suffering from DD depends on knowledge increase and technology improvement which evolve in tight connections. Gathering cohorts of patients affected by similar disorders allowed to search for a shared molecular disorder while identification of genetic variants having similar predicted consequences allowed to describe phenotypic spectrum of syndromes which had not been previously clinically identified and to decipher some heterogeneous disorders. Diagnosis yield of DD could be assessed from around 5-15% with chromosomal analyses (especially microarrays) to 40% by means of exome sequencing which targets gene coding regions. Despite these improvements, genetic cause remains unknown in many patients, in part due to undetectable mutational mechanisms with used technologies, but also because of interpretation limits in sequencing data although pathogenic variants were detected.This phD aims at going on the research effort of new mutational spectrum of known disease-causing genes and identification of new ones, after non-contributive diagnosis analyses. This work consisted in exome reanalysis either in a recognizable cohort of ID associated with marfanoid features, or in a cohort of patients with non-syndromic ID. Otherwise, from a cohort of unexplained sporadic DD patients after solo exome reanalysis, we sequenced exome of both parents to interpret in a trio-based strategy. Every time a candidate gene was suspected, it was searched for recurrence in our in-house exome database and through international datasharing platforms to strengthen the association with the disorder and describe the phenotypic spectrum ; functional analyses were conducted when necessary to argue for the pathogenicity.This strategy allowed to identify several candidate genes which involvement in the disorders could be confirmed in a large proportion of them and led to scientific publications, either after works entirely conducted within our lab (DLG4 truncating variants identified in 3 patients from the marfanoid ID cohort), or by means of international collaborations: new mutational mechanism and new inheritance associated with KCNQ3 confirmed by functional analyses (ID, seizures, consanguinity), trio-exome reanalysis in a cohort of 70 unexplained sporadic DD patients allowing to identify a strong candidate gene in 26% of them (including KCNMA1, FBXO11, HNRNPR), and variants of unknown significance in 14%, with 3/70 patients probably affected by multiple disorders.These results confirm the great interest of exome reanalysis and datasharing to improve new pathogenic variants and new disease-causing genes.
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Sébastien Moutton. L'approche basée sur le génotype déterminé par séquençage haut-débit en première intention et le partage international des données pour identifier de nouveaux gènes et nouveaux syndromes responsables d'anomalies du développement. Médecine humaine et pathologie. Université Bourgogne Franche-Comté, 2019. Français. ⟨NNT : 2019UBFCI013⟩. ⟨tel-02477164⟩

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