Genetic Predisposition to Sudden Cardiac Death: A Molecular Cardiology Study

Abstract

Sudden cardiac death (SCD) remains a major global health challenge, and increasing evidence highlights the critical role of genetic predisposition in modulating individual susceptibility. This molecular cardiology study systematically investigated pathogenic, likely pathogenic, and risk-associated variants across key cardiac ion-channel, desmosomal, and sarcomeric genes to determine their contribution to inherited arrhythmogenic risk. Using next-generation sequencing and functional molecular assays, we identified a significantly elevated burden of deleterious variants in KCNQ1, SCN5A, RYR2, PKP2, and LMNA among individuals with a documented family history of SCD. Quantitative variant impact modelling revealed that mutations affecting ion-channel gating kinetics and intracellular calcium handling were strongly associated with abnormal electrophysiological responses, including prolonged repolarization (QTc > 480 ms), conduction delays, and increased arrhythmic triggers. Moreover, genotype–phenotype correlation analyses demonstrated that carriers of compound or multiple heterozygous variants exhibited a 2.7-fold higher risk of malignant arrhythmias compared to single-variant carriers. Functional characterization further confirmed that several novel variants resulted in reduced channel current density, impaired desmosomal integrity, and destabilized myocardial structural proteins, collectively driving electrical instability. Overall, the results of this study underscore the substantial contribution of inherited genetic abnormalities to SCD vulnerability and highlight the importance of integrating molecular genetic screening with clinical risk stratification. The identification of high-impact variants and their mechanistic consequences provide a foundation for targeted surveillance, family cascade screening, and future gene-directed therapeutic interventions.