The evolution of gene‐guided management of inherited arrhythmia syndromes: Peering beyond monogenic paradigms towards comprehensive genomic risk scores

Abstract

Inherited arrhythmia syndromes have traditionally been viewed as monogenic forms of disease whose pathophysiology is driven by a single highly penetrant rare genetic variant. Although an accurate depiction of a proportion of genetic variants, the variable penetrance frequently noted in genotype positive families and the presence of sporadic genotype negative cases have long highlighted a more nuanced truth being operative. Coupled with our more recent recognition that many rare variants implicated in inherited arrhythmia syndromes possess unexpectedly high allele frequencies within the general population, these observations have contributed to the realization that a spectrum of pathogenicity exists among clinically relevant genetic variants. Notably, variable mutation pathogenicity and corresponding variable degrees of penetrance emphasize a limitation of contemporary guidelines, which attempt to dichotomize genetic variants as pathogenic or benign. Recognition of the existence of low and intermediate penetrant variants insufficient to be causative for disease in isolation has served to emphasize the importance of additional genetic, clinical, and environmental factors in the pathogenesis of rare inherited arrhythmia syndromes. Despite being rare, it has also become increasingly evident that common genetic variants play critical roles in both heritable channelopathies and cardiomyopathies and in aggregate may even be the primary drivers in certain instances, such as genotype negative Brugada syndrome. Our growing realization that the genetic substrates of inherited arrhythmia syndromes have intricacies that extend beyond traditionally perceived monogenic paradigms has highlighted a potential value of leveraging more comprehensive genomic risk scores for predicting disease development and arrhythmic risk.

Comparing the performance of risk stratification scores in Brugada syndrome: a multi-centre study

“…( 21) By contrast, a family history of SCD is a marker for intermediate risk is likely due to the polygenic inheritance, variable expression and incomplete penetrance in BrS. (22) Whilst the presence of pathogenic SCN5A mutation increases the risk of BrS manifestation, clinical and environmental factors are required to drive the degree of electrophysiological dysfunction across the disease threshold. (23,24) Although genetic data were not examined in the present study, the predictive value of genetic and genomic findings should be explored in the future (25).…”

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

“…(2) Calcium Channel . By reducing Ca2+ influx, GFA reduced the depolarization rate and average repolarization rate of cardiomyocytes [ 125 ]. GFA mainly acted on the inactive state of the L-type calcium channel, which prolonged recovery time from the inactivation state.…”

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

“…The etiology of cardiac arrhythmias is complex, encompassing genetic predispositions, environmental influences, the remodeling of cardiac tissue, and lifestyle factors [1]. Advancements in genomic research have significantly contributed to unraveling the genetic foundations of arrhythmias, shedding light on their complex pathophysiology and paving the way for novel therapeutic approaches [2]. Atrial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is associated with increased risks of heart failure, dementia, stroke, and death [3,4].…”