Mutation-specific roles of sustained sodium current (INa) in guiding precision medicine for long QT syndrome type 3

Long QT syndrome type 3 (LQTS3), caused by gain-of-function mutations in the <i>SCN5A</i> gene, encompasses a spectrum of clinical presentations, ranging from asymptomatic carriers to severe arrhythmic phenotypes, representing the "silent killer" and "brutal killer" dichotomy. The p.I239V mutation is associated with mild symptoms and minimal arrhythmic events, whereas the newly identified p.M1487K mutation is linked to life-threatening arrhythmic storms. This study aimed to explore the electrophysiological properties of these mutations and their responses to sodium channel blockers to advance precision medicine in LQTS3 management. Genetic analysis identified rare <i>SCN5A</i> mutations in two LQTS3 patients. Site-directed mutagenesis was used to construct mutant <i>SCN5A</i> plasmids, which were expressed in HEK293 cells. Electrophysiological properties were analyzed using patch-clamp techniques, and pharmacological responses to flecainide, mexiletine, and ranolazine were evaluated. Electrophysiological recordings correlated with clinical presentations. Both mutations showed increased window I_Na and faster recovery from inactivation. The p.I239V mutation lacked sustained I_Na, while p.M1487K exhibited significantly increased sustained I_Na (2.3 ± 2.15%, <i>P</i> < 0.0001). Mexiletine and ranolazine effectively reduced sustained I_Na by 76.15 ± 5.83, and 77.63 ± 9.41%, respectively, outperforming flecainide, aligning with clinical responses. This study highlights the role of sustained I_Na in LQTS3 severity and underscores the importance of mutation-specific treatments. By tailoring treatments to the electrophysiological characteristics of each mutation, precision medicine offers a promising approach to improving patient outcomes in LQTS3.