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Déterminisme moléculaire du développement des membres : apport des nouvelles technologies d’étude du génome

Abstract : Limbs development is a complex process of which mecanism is today only partially known. Embryological development abnormalities of genetic origins are rare entities. Such abnormalities can be unique or multiple, single or syndromic, sporadic or of family origins.The study of large cohorts of patients carrier of limb extremities malformations is an excellent tool that allows an identification of the genes or regulatory elements involved in their pathology and consenquently, in the development of the limb. In most of the cases, the genetic event involved is a point mutation in the genes coding transcriptionnal factor or regulatory sequence. However, variations in the number of copies are also involved.Today, new technologies of genome study, from high through put sequencing of a target genes panel to a whole exome or genome sequencing, can allow an identification of these new targets. It is thank to these technological advances that we decided to study the moleculary determinism of limbs development. To do so, we analyzed a very large cohort of 684 patients, all carriers of a limb malformation, through different genes panels, of different sizes, but also through a whole exome analysis and a pangenomic CGH array.The results of this work allowed us, in the first part, to establish a genes panel, suitable to a molecular analysis laboratory, to the bioinformatic analysis with an optimized cost, and that can identify the SNVs but also the CNVs in only one analysis.On a second part, we managed to identify 5 genes, not yet described in human pathology, which seemed to have a role in limb development. For one of these genes a promising functional analysis has started.
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Anne-Sophie Jourdain. Déterminisme moléculaire du développement des membres : apport des nouvelles technologies d’étude du génome. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2019. Français. ⟨NNT : 2019LIL2S037⟩. ⟨tel-02860071⟩

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