Development of a functional assay to determine the pathogenicity of genetic variants with unknown significance identified in patients with cardiac arrhythmia.

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 fainting and sudden cardiac death. At present, over 50 ICA genes have been identified. With the advent of next generation sequencing technology it is possible to test all of these genes simultaneously in multiple ICA patients with a single test. This method proficiently identifies clear disease causing genetic alterations. However, as the number of genes involved increases through better mechanistic insight into disease modifier genes and polymorphisms, we are confronted with a high number of genetic alterations for which causality is unsure. These pose a major challenge for the management of ICA patients. Therefore, the aim of this project is to develop a functional tool that will allow to test the functional impact of variants of unknown significance. We have developed a zebrafish assay in which the electrical dynamics of the heart are reported by fluorescent light signals. As zebrafish are translucent in early development, this model lends itself perfectly to visualize these signals 'in vivo' and at an exceptional resolution. After validating this tool with known pathogenic alterations, we will apply this method to evaluate variants of unknown significance and test the possible arrhythmogenic side effects of some drugs. This innovative approach will allow the clinicians to deliver true personalized medicine.

Keywords:CARDIAC ARRHYTHMIA, PATHOGENESIS

Disciplines:Cardiac and vascular medicine, Urology and nephrology

Project type:Collaboration project