Association Between Deleterious SCN5A Variants and Ventricular Septal Defect in Young Patients With Brugada Syndrome

This study aimed to investigate the clinical characteristics of young patients with Brugada syndrome (BrS) with ventricular septal defect (VSD) and explore their genetic backgrounds.

VSD is the most frequently occurring congenital heart disease among children. In contrast, BrS is a rare hereditary disease that is responsible for ventricular fibrillation and sudden cardiac death. Owing to their low incidence, the genetic background and clinical characteristics of patients with BrS with VSD have not been elucidated yet.

This study enrolled 36 individuals who were diagnosed with BrS when they were <20 years of age and performed genetic screening for SCN5A. The functional alteration in mutant Na⁺ channels was confirmed by patch clamp technique.

Among the 36 patients with BrS, 5 had been diagnosed with VSD. This study found 14 heterozygous SCN5A variants in 15 unrelated patients. The 5 patients with VSD carried SCN5A variants, including R367S, R535∗, R893C, W1345C, and G1743R. The 3 missense variants (R893C, W1345C, and G1743R) have been proved to reduce peak Na⁺ current to <10%. A functional analysis of SCN5A R367S was performed and the variant was found to be nonfunctional.

This study identified 5 loss-of-function SCN5A variants in 5 young patients with BrS with VSD. The study hypothesizes that altered blood flow in the right ventricular outflow tract leads to fibrosis and electrophysiological changes, predisposing the patients to earlier clinical presentation of BrS. In patients with VSD and ST-segment elevation in the right precordial leads, BrS should be considered and appropriate screening should be pursued accordingly.