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Next generation phenotyping and genotyping in inherited primary cardiac arrhythmia syndromes and cardiomyopathies

The relation between the genotype and phenotype of primary arrhythmia syndromes (PAS) and cardiomyopathies (CMP) is complex and ever expanding. In the first part of this thesis project, we evaluated the value of both novel and existing electrocardiographic parameters in the diagnosis and prognosis of these patients. We proposed a novel method for evaluation of the QT interval based on the patient’s own QT rate dependence profile obtained from 24 hour holter recordings (Chapter 1). This individualized QT interval (QTi) is an easy to measure method that proofed to have high diagnostic accuracy in genotyped patients with long QT syndrome (LQTS), both in our own population of LQTS patients as in a large validation cohort. Patients with loss-of-function SCN5A mutations show diverse phenotypes including Brugada Syndrome (BrS), a progressive cardiac conduction disease and premature atrial fibrillation or flutter (chapter 2). The risk of sudden cardiac death (SCD) in patients who don’t show a type 1 Brugada ECG in rest or after provocation with sodium channel blockers has not been extensively studied, but has traditionally been regarded as low. We showed that loss-of-function SCN5A mutation carriers had an annual incidence of SCD of 1.37%. Remarkably, 75% of these patients suffering SCD did not have a type 1 ECG warranting proper follow-up of these patients. However, risk markers for SCD in this population should be assessed in larger cohorts. We evaluated the value of the index of cardio-electrophysiological balance (iCEB), which might serve as an ECG-based derivative of cardiac wavelength λ and measured as QT interval divided by QRS duration, as a novel potential biomarker of arrhythmic risk (chapter 3). iCEB was significantly altered in opposite directions in situations with increased risk for torsadogenic ventricular tachycardia (VT) or non-torsadogenic (VT). In hypertrophic cardiomyopathy, neither QTi, QT rate dependence or iCEB were significant predictors of SCD (chapter 4). However, on top of traditional risk stratification variables, we identified male gender and the presence of negative T waves in the inferior leads as marker of increased risk of SCD. A score to predict the a priori chance of carrying a disease-causing mutation in HCM based on clinical variables was constructed (chapter 5). Such a score aids in proper genetic counselling. In the second part of the project we evaluated the additional value of next generation sequencing (NGS) techniques in PAS and CMP. Panel based NGS resulted in a genetic diagnosis in 20% of index patients in whom prior evaluation with Sanger sequencing or mutation scanning techniques of the main genes implicated in their specific phenotype had remained negative (chapter 6). The increased detection rate was due to sequencing of novel genes in 52% of the cases and due to technical failures with the historical analysis in 48%. Finally, as a proof of concept, we identified a novel RBM20 mutation with whole exome sequencing in a large family with dilated cardiomyopathy in whom prior panel based NGS had remained negative (chapter 7).

Date:1 Oct 2013  →  19 Dec 2017
Keywords:Next generation sequencing, QT rate dependence, Individualized QT
Disciplines:Cardiac and vascular medicine
Project type:PhD project