Abstract
Inherited Cardiac Arrhythmia (ICA) refers to a group of genetic disorders in which patients present with abnormal and potentially harmful heart rhythm. These episodes often go unnoticed, but can lead to sudden cardiac death. At present, over 60 ICA genes have been identified. Using novel next-generation sequencing technology it is possible to screen all ICA genes in a single molecular diagnostic test. This analysis allows the identification of clear disease-causing variants in patients, but also results in detection of a high number of genetic variants for which causality is unsure. These pose a major burden for the management of ICA patients. Therefore, the aim of this project is to develop a functional tool that allows to test the functional impact of these so-called 'variants of uncertain significance' (VUS).
We will create an advanced model of 'human induced pluripotent stem cells (hiPSC)' with built-in special fluorescent proteins that report on calcium and voltage signals. Starting from these hiPSCs we will generate cardiomyocytes, cardiac fibroblasts and endothelial cells that we grow in a controlled mixture into cardiac microtissues (cMT). The electrical activity and calcium handling of these cMTs can then be monitored with a specialized confocal fluorescence microscope. To validate our tool, we will first introduce known disease-causing alterations into the genome of these transgenic hiPSCs and study the effect on the electrical activity of the derived cMTs. Next, we will apply this method to evaluate the functional effect of VUS identified in patients. This innovative approach will improve the molecular diagnostics of inherited cardiac arrhythmias and allow clinicians to deliver true personalized medicine.
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