Cardiogenetics: the role of genetic testing for inherited arrhythmia syndromes and sudden death

Abstract

There have been remarkable advances in our knowledge of the underlying heritability of cardiac arrhythmias. Long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, progressive cardiac conduction disease and the short QT syndrome comprise the inherited arrhythmia syndromes (IASs). Pathogenic variants in cardiac ion channel and calcium handling protein genes lead to these conditions, usually in the absence of overt structural cardiac disease. Diagnosis is contingent on the ECG phenotype but genetic testing may help to confirm the diagnosis and provide information on the mechanism of arrhythmogenesis that may guide treatment and provide prognostic information in relation to the risk of sudden arrhythmic death. Clinical genetic testing uses ‘panels’ of genes that are the likely culprits for the IASs being investigated. An International Consortium (Clinical Genome Resource) has curated gene panels based on genetic and experimental evidence of causation of inherited conditions and that have a role in clinical genetic testing. A ‘single gene’ or monogenic basis for IASs exists but in future, missing heritability and incomplete penetrance will be uncovered by association of common variants through genome-wide association studies. Novel rare variants will also be detected through whole-genome sequencing. The formulation of polygenic risk scores will likely help to predict phenotypic expression and response to treatments/risk stratification and move genetic testing very much to the fore of the diagnostic process.

Fetal Arrhythmia Leading to a Diagnosis of Congenital Long QT Syndrome Type II

“…LQT2 is associated with pathogenic variants in the KCNH2 gene causing loss of function in the delayed rectifier channel K V 11.1 governing the rapid outward current of potassium ions (I Kr ). 4 This results in the prolongation of phase 3 of the ventricular action potential and subsequent QT interval prolongation.…”

Genetic causality between type 1 diabetes and arrhythmia: a two-sample Mendelian randomization study

“…Arrhythmia can be classi ed according to anatomical site, dysfunction, etiology, and severity, and the study could not perform a more detailed analysis of arrhythmia subtypes. Similarly, a gender-speci c analysis could not be performed (32) and it is not possible to exclude those cases with arrhythmias that are clearly genetically related (33). However, the dataset included all patients who met the diagnosis of arrhythmia.…”

Application of next generation sequencing in cardiology: current and future precision medicine implications

“…They include Brugada syndrome, Long QT syndrome (LQTS), Short QT syndrome (SQTS), and Catecholaminergic polymorphic ventricular tachycardia (CPVT). They are caused by alterations in genes involved in the ion channels, present in cell membranes and various organelles (53).…”