Physiology-Centered Genomic Profiling of High-Impact Potassium Channel Variants in Sudden Unexplained Death: Mechanistic Disruption of Cardiac Repolarization

Rationale: Sudden unexplained death (SUD) in individuals with structurally normal hearts remains a major diagnostic gap in cardiovascular medicine. Potassium channels are central to cardiac repolarization and metabolic–electrical coupling; pathogenic variants affecting conductance, gating, or channel assembly may destabilize electrophysiological homeostasis and precipitate lethal arrhythmias. A physiology-guided molecular framework is essential for clarifying arrhythmogenic substrates and improving postmortem diagnostics and familial risk stratification. Hypothesis: We hypothesized that high-severity SUD cases harbor rare pathogenic variants in cardiac potassium channel genes that disrupt electrophysiologically critical domains and trigger repolarization failure in the absence of structural pathology. Objective: To characterize potassium channel gene variants in SUD cases and interpret their electrophysiological impact through domainspecific mapping, thereby elucidating mechanistic drivers of fatal repolarization failure and informing future molecular autopsy and population-level screening strategies. Methods: Demographic and clinical data were collected from forensic SUD cases. Postmortem blood samples were obtained from 43 adjudicated SUD individuals (age ≥24 years; mean 35.0 ± 6.2; 93.02% male) with structurally normal hearts confirmed through full autopsy and toxicological assessment. Targeted Next-generation sequencing (NGS) of six major cardiac potassium channel genes (KCNH2, KCNQ1, KCNE1, KCNJ2, KCNJ5, KCNJ8) was performed. Variant interpretation incorporated ClinVar, in silico functional prediction, and physiology-centered domain mapping to infer disruptions in the critical architecture of repolarization. Results: Clinically, 58.14% of deaths occurred during sleep, consistent with heightened arrhythmogenic susceptibility during autonomic and circadian modulation. A notable geographic clustering was observed: 21 of 43 cases originated from Northeast Thailand, suggesting potential regional genetic enrichment. Anthropometric measures (168.5 ± 6.6 cm; 62.7 ± 10.8 kg) were within normal ranges, supporting a non-metabolic phenotype. Three pathogenic or likely pathogenic variants were identified. Two KCNH2 variants—a pore-loop mutation (p.G628S) associated with diminished IKr conductance and a splice site mutation (c.2592+1G>A) predicted to impair channel assembly—converge on phase 3 repolarization instability. A KCNJ8 variant (p.G238R) disrupts the ATP-sensitive and inward rectifier domain essential for metabolic–electrical coupling under stress. All variants localized to electrophysiologically high-impact domains, offering coherent mechanistic explanations for sudden electrical collapse. Conclusion and Future Directions: This physiology-centered genomic investigation reveals convergent potassium channel dysfunction as a mechanistic substrate for SUD. Future work will incorporate patch clamp electrophysiology, structural modeling, and—given the high regional concentration in Northeast Thailand—population genetic and ethnogenomic mapping to refine genotype–phenotype understanding and guide preventive strategies in at-risk populations. Funding: Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University (Grant No. RA60/050) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.