Decoding the genetic puzzle of inherited cardiac arrhythmias : insights from molecular autopsy, genetic profiling and iPSC-derived cardiomyocyte modelling
Inherited cardiac arrhythmias (ICA) encompass a group of cardiac diseases with common characteristics such as low prevalence, reduced penetrance and variable phenotypical expression including electrocardiogram abnormalities, syncopes, ventricular fibrillations and increased risk for sudden cardiac death (SCD). Approximately 70 genes contribute to ICAs, demonstrating substantial genetic overlap. Despite advancements in next-generation sequencing (NGS), many cases remain genetically unsolved due to complex inheritance patterns and variants of uncertain significance (VUS) in known genes. Functional analyses can provide the ultimate proof to reclassify a VUS but as this is labour intensive and expensive and not routinely done in a diagnostic setting. A case of SCD was investigated using NGS gene panels. We detected two VUS in the KCNQ1 and DSG2 genes. An in vitro functional analysis of the KCNQ1 variant did not show any effect on the potassium current. Segregation analysis revealed that the DSG2 variant was de novo, upscaling its classification to likely pathogenic. In only 30% of Brugada Syndrome (BrS) patients a genetic cause is identified. We analyzed 350 patients and found (likely) pathogenic variants in 9%. These patients showed more severe clinical features. Utilizing the Shanghai scoring system for definite BrS diagnosis increased yield to 18%. 31% of all the patients carried a VUS but such VUS do not contribute to more informative genetic counselling for the patient. Induced pluripotent stem cells (iPSCs) emerged as a valuable human cellular model. iPSCs, derived from Brugada syndrome patients with a specific SCN5A mutation, displayed pluripotency and validated through molecular assays. Despite sharing the same Belgian SCN5A founder mutation, patients exhibited diverse clinical phenotypes. Differentiated into cardiomyocytes, patient iPSC-CMs showed variations in SCN5A transcripts but similar total expression, sodium current, and action potential characteristics compared to controls. Notably, statistical analysis challenges arose from significant variability between iPSC clones and individuals. The use of a CRISPR-generated isogenic control underscores the promising utility as a strategy for studying mutations in Brugada syndrome. With enhanced molecular techniques for investigating the genetic landscape of ICAs, it has become clear that the effect of genetic variants is not always easy to interpret and functional analysis is needed. For this purpose, novel study models such as iPSC-CMs can play an important role as they represent the disease-relevant cell type with full cardiomyocyte-specific molecular machinery, can be patient-specific and isogenic lines can be generated. In this way, also more complex interactions can be studied in a relevant cell model.
Antwerp : University of Antwerp, Faculty of Medicine and Health Science , 2024
201 p.
Supervisor: Alaerts, Maaike [Supervisor]
Supervisor: Loeys, Bart [Supervisor]
Supervisor: Schepers, Dorien [Supervisor]
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Creation 29.02.2024
Last edited 08.03.2024
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