City Research Online

Abstract

Introduction: Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited arrhythmia syndromes that cause sudden cardiac death. SCN5A-E1784K, the most common LQTS- and BrS-associated SCN5A mutation, has a variable phenotype that presents challenges in clinical management. Risk features in this mutation have not been reported, and while functional characteristics have been studied in heterologous cell lines, there is limited data in patient-specific models.

Aims: 1) To study clinical characteristics, risk features, common genetic variants and genetic risk scores associated with phenotype in a large international SCN5AE1784K cohort, and 2) study phenotype-specific properties of this mutation in vitro using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) from SCN5A-E1784K carriers with extremes of phenotype.

Methods: Single nucleotide polymorphisms (SNPs) previously associated with ECG traits were genotyped. Association of phenotypic characteristics with risk and common genetic variants were studied. Integration-free hiPSC-CMs were produced from dermal fibroblasts of SCN5A-E1784K carriers with extremes of phenotype and a healthy control. These cells were characterised. Nav1.5 expression and action potential characteristics were studied in vitro.

Results: Cardiac conduction (QRS duration) was the only independent marker of risk in SCN5A-E1784K. SNP associations with phenotype were inconsistent and varied with ethnicity. Genetic risk scores were, however, associated with BrS phenotype and QRS duration transethnically. Integration-free hiPSC lines were derived from two SCN5A-E1784K carriers with extremes of phenotype and each line was differentiated to hiPSC-CMs, laying the foundation for future work. There was a trend towards reduced Nav1.5 expression in the BrS line compared to the LQT3 line and the control line. Electrophysiological results were limited by cellular heterogeneity.

Discussion: This project has provided insight into clinical features of risk, common genetic modifiers of phenotype, and genetic mechanisms of BrS/LQTS genotype/phenotype correlation in SCN5A-E1784K. These findings, and planned future work, can help guide personalised patient management in clinic.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > Q Science (General)
Departments:	School of Health & Medical Sciences > Cardiovascular and Genomics Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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