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Identification de nouveaux variants responsables d'arythmies cardiaques avec risque de mort subite

Abstract : Cardiac sudden death is due to ventricular tachycardia (VT) degenerating into ventricular fibrillation and asystole. Life-threatening arrhythmias are mostly associated with structural heart abnormalities or ischemia. In contrast, there are patients with no ECG abnormalities at basal level, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) or short-coupled torsades de pointes (scTdP). The first aim of my thesis was to study the genetic origin of scTdP through exome sequencing of 20 patients. This study allowed us to show the genetic heterogeneity of this pathology, but also to identify a large proportion of variants involved in the cardiac calcium regulation. Among all identified variants, we analyzed a CACNA1C loss-of-function variant inducing a reduction in current density of the L-type calcium current and an increase of its voltage-dependent inactivation. This variant, present in 0.8% of the African population, is a new risk factor for ventricular arrhythmias. Functional studies were focused on 3 RYR2 variants leading to channel hyperactivity in patients with TdPcc and the identification of a loss-of-function variant present, for the first time, at the homozygous and the heterozygous states in two families with CPVT. This last variant lead to a blunted response to adrenergic stimulation. This work provided a better understanding of the genetics of scTdP and allowed us to show the involvement in scTdP of two genes already implicated in ventricular arrhythmias, CACNA1C and RYR2. The present studies confirm that RYR2 variants are responsible for several phenotypes associated with cardiac arrhythmias leading to sudden death.
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Submitted on : Tuesday, June 16, 2020 - 1:00:08 PM
Last modification on : Tuesday, September 1, 2020 - 3:21:39 AM


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  • HAL Id : tel-02869914, version 1


Malorie Blancard. Identification de nouveaux variants responsables d'arythmies cardiaques avec risque de mort subite. Génétique des populations [q-bio.PE]. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS406⟩. ⟨tel-02869914⟩



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