| dc.description.abstract | Arrhythmias are abnormal heart rhythms that represent a major cause of morbidity and mortality across the world. While environmental factors such as lifestyle, diet, and other exposures may influence disease susceptibility, a substantial contribution arises from genetic variation in the form of ‘inherited arrhythmia syndromes’. Rare variants in cardiac ion channels and sarcomeric proteins may affect heart cell electrophysiology, and lead to potentially fatal arrhythmias responsible for sudden cardiac death. Despite this gene-disease link, it often remains difficult to ascertain the risk associated with specific variants in those genes. This is often because of an incomplete mechanistic view of how such variation may affect RNA transcript composition or translated protein properties. This is a challenging clinical problem, as optimal medical management is commonly thwarted by such incomplete knowledge. Indeed, a vision for human genetics is genotype-first care, where understanding variant effect can guide care for all patients who harbor such a variant. Towards this goal, I present experimental, computational, and clinical investigations into inherited arrhythmia syndromes caused by large effect, rare variants in the genes SCN5A, KCNH2, KCNQ1, and FLNC. These genes are associated with Brugada Syndrome, Long QT Syndrome, and Arrhythmogenic Cardiomyopathy. Many investigations are empowered by novel technologies that have enabled interrogation of variant effect at scale (SyncroPatch and ParSE-seq) or at high resolution (CRISPR-Cas9 and induced pluripotent stem cell-cardiomyocytes). Several of these investigations lead to the development of general methods that could be applied in many distinct disease areas. Most importantly, the studies directly help refine the path of clinical management for individuals harboring the variants in this work. | |
