VENTRICULAR arrhythmia genetic risk is becoming increasingly important in cardiovascular medicine as research uncovers how different genomic layers contribute to susceptibility to sudden cardiac death (SCD). Although cardiomyopathy and arrhythmia (CMAR) gene panels assist clinical management, many high-risk patients still lack a clear genetic diagnosis. Whole-genome sequencing now offers a deeper understanding of this complexity.
Ventricular arrhythmia drivers across the genome
In a detailed study involving 523 high-risk individuals and 596 controls, researchers evaluated common, rare, and ultrarare variants across ion channel, structural, and epilepsy-associated genes. This approach demonstrated that ventricular arrhythmia genetic risk arises not from a single variant class but from an additive combination of genetic influences. Secondary keywords such as polygenic risk scores, rare noncoding variants, and cardiomyopathy genes are central to interpreting these findings.
Polygenic risk scores drawn from 18 cardiac-related traits showed strong associations with arrhythmia outcomes. Genetic predisposition to QRS prolongation and extended QTc, both recognised predictors of SCD, was higher in affected individuals. Conversely, controls exhibited higher genetically predicted left ventricular ejection fraction, reflecting the established relationship between ventricular dysfunction and arrhythmic disease. These observations highlight how polygenic background alters disease penetrance and expressivity.
Rare and regulatory variants expanding understanding
Rare variant analysis across 377 CMAR and epilepsy genes supported an omnigenic model in which multiple biological pathways, such as proteostasis and cytoskeletal signalling, sensitise individuals to arrhythmia risk. The study also identified a significant excess of ultrarare regulatory variants associated with cardiomyopathy, arrhythmia, and epilepsy genes. These variants, often missed by typical panel sequencing, can disrupt transcription factor binding or enhancer activity, subtly altering gene expression and contributing to disease risk.
Clinical impact and future direction
A cumulative variant score integrating all genomic layers effectively identified high-risk individuals, independent of primary pathogenic variants. This Genomic Additive Polygenic Score (GAPS) provides a more accurate, probabilistic assessment than simple genotype-positive or negative classifications.
As WGS becomes more accessible, integrating panel-based sequencing with targeted arrays may allow comprehensive ventricular arrhythmia genetic risk profiling in routine clinical care. Such tools could refine implantable defibrillator decisions, support precision treatment strategies, and significantly improve outcomes for those with inherited cardiac conditions.
Reference
Monroe TO et al. A combined genomic arrhythmia propensity score delineates cumulative risk. Cell Rep Med. 2025;DOI:10.1016/j.xcrm.2025.102455.
