Research team
Elucidating the pathogenicity of genetic variants of uncertain significance in Brugada syndrome patients by functional modelling in hiPSC-derived cardiomyocytes and zebrafish.
Abstract
Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels result in detection of numerous genetic "Variants of Uncertain Significance" (so called VUS), but currently functional models to prove their causality are lacking. Therefore, in my project I will create two proof-of-concept models for a known pathogenic CACNA1C mutation associated with BrS: a cardiomyocyte cell model, created from human stem cells, and a novel transgenic zebrafish model with built-in fluorescent calcium and voltage indicators. By functionally characterising these models with innovative imaging and electrophysiological techniques, I will assess the mutation's effect on a cellular level and in the whole heart, proving its contribution to disease causation. After validating these models, I will apply this strategy to functionally assess the pathogenicity of two VUS identified in two BrS patients. Ultimately, by establishing the use of these state-of-the-art study models to predict the pathogenicity of BrS-related VUS, a more accurate risk stratification and proficient use of specialized prevention strategies can be implemented in the future, potentially also for other electrical disorders of the heart.Researcher(s)
- Promoter: Loeys Bart
- Co-promoter: Alaerts Maaike
- Co-promoter: Knapen Dries
- Co-promoter: Labro Alain
- Co-promoter: Schepers Dorien
- Co-promoter: Snyders Dirk
- Fellow: Vandendriessche Bert
Research team(s)
Project type(s)
- Research Project
Elucidating the pathogenicity of genetic variants of uncertain significance in Brugada syndrome patients by functional modelling in hiPSC-derived cardiomyocytes and zebrafish.
Abstract
Brugada syndrome (BrS) is an inherited arrhythmic disorder and is estimated to account for up to 12% of all sudden cardiac death cases, especially in the young (< 40 years old). Only in circa 30% of BrS patients the underlying genetic cause can be identified with current diagnostic arrhythmia gene panels. Moreover, the use of these panels result in detection of numerous genetic "Variants of Uncertain Significance" (so called VUS), but currently functional models to proof their causality are lacking. Therefore, in my project I will create two proof-of-concept models for a known pathogenic CACNA1C mutation associated with BrS: a cardiac muscle cell-model, created from human stem cells, and a novel transgenic zebrafish model with built-in fluorescent calcium and voltage indicators. By functionally characterising these models with innovative imaging techniques, I will assess the mutation's effect on a cellular level and in the whole heart, proving it's contribution to disease causation. After validating these models, I will apply this strategy to functionally assess the pathogenicity of two VUS identified in two BrS patients. Ultimately, by establishing the use of these state-of-the-art study models to predict the pathogenicity of BrS-related VUS, a more accurate risk stratification and proficient use of specialized prevention strategies can be implemented in the future, potentially also for other electrical disorders of the heart.Researcher(s)
- Promoter: Loeys Bart
- Co-promoter: Alaerts Maaike
- Co-promoter: Schepers Dorien
- Fellow: Vandendriessche Bert
Research team(s)
Project type(s)
- Research Project