GENETIC CAUSES OF CARDIAC CHANNELOPATHIES IN QATAR: TOWARD RISK STRATIFICATION AND MANAGEMENT STRATEGIES OF DISEASE

Abstract

Background: Cardiac channelopathies are inherited disorders caused by pathogenic variants in genes encoding cardiac ion channels, disrupting ion currents, and leading to heart arrhythmias without structural heart defects. These channelopathies, including Long QT syndrome, Catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and Short QT syndrome, are significant contributors to cardiac arrhythmias and sudden cardiac death, with genetic testing playing a pivotal role in diagnosing and managing these electrophysiological disturbances. Aim: The study aims to identify potential genetic causes for the development of cardiac channelopathies in the understudied population of Qatar, taking into account the high level of consanguinity and inbreeding in this region of the world, thus paving the way toward risk stratification and management strategies of the disease. Method: Whole-genome sequencing (WGS) using NovaSeq platform 6000 was performed on 16 patients diagnosed with cardiac channelopathies at Sidra Medicine in Qatar, in addition to 56 of their relatives, followed by data segregation analysis and variant filtration. Results: We identified four known pathogenic and likely pathogenic variants in the PTPN11, TECRL, SCN5A, and KCNQ1 genes, explaining the conditions in four (25%) of our cardiac channelopathy patients. Additionally, three pathogenic variants were found in the UFM1, ITPR3, and VPS13B genes, which are potentially novel. Although these genes are not directly linked to cardiac phenotypes, the variants discovered could represent novel findings. Moreover, six patients were found to carry at least one variant of uncertain significance (VUS) in various genes previously associated with cardiac phenotypes, which could explain the cardiac channelopathies. Among these gene variants, de novo variants in BCL9, KAT6B, and CCND1 genes that were detected in three of our patients are potentially novel as they were not reported in any of the tested populations and clinical datasets, which may contribute to the phenotype. Conclusion: Our findings revealed the complex genetic basis of cardiac channelopathies in the population of Qatar, highlighting the importance of pursuing region-specific genetic research. The data also reinforce the need for further functional studies to understand the role of some of the identified variants in the pathogenesis of the disease.