Association between genetic variants and electrocardiographic phenotype in Brugada syndrome

Introduction

Brugada syndrome (BrS) is a rare cardiac disorder associated with ventricular arrhythmias and sudden cardiac death. Diagnosis relies on a type 1 ECG pattern, defined by ≥0.2 mV J-point elevation with a negative T wave in V1–V2, either spontaneous or drug-induced (usually by ajmaline). Genetically, a definite causal role has been established only for SCN5A, encoding the cardiac voltage-gated sodium channel. The contribution of other genes remains debated.

Aim

To assess the association between genetic variants in SCN5A and other ion channel–related, structural, or regulatory genes and ECG phenotype expression in BrS, and secondarily their relationship with clinical and electrophysiological parameters linked to arrhythmic risk.

Methods

Patients referred for suspected BrS (excluding relatives of probands) were classified into four ECG pattern groups: non-diagnostic, drug-induced, spontaneous intermittent, and spontaneous persistent. Genetic testing was performed by SCN5A Sanger sequencing, NGS gene panels, or whole-exome sequencing (WES). Variants were classified as VUS, VUS with likely pathogenicity (VUS/LP), or likely/pathogenic (LP/P). Genetic positivity was defined as LP/P (standard) or "likely causative" (VUS/LP + LP/P). A subgroup underwent EP study to evaluate low-voltage areas, right ventricular refractory period heterogeneity and VT/VF inducibility.

Results

The study included 284 patients (median age 45.5 years, IQR 33–55; 67.3% male): 49 (17.3%) non-diagnostic for BrS, 95 (33.5%) drug-induced, 103 (36.3%) spontaneous intermittent, and 37 (13.0%) spontaneous persistent. Genetic variants were found in 83 patients (29.2%), including 26 (9.2%) with LP/P and 52 (18.3%) with "likely causative" variants. Palpitations were more frequent in the spontaneous intermittent than in the persistent pattern (p = 0.02); low-voltage areas were also more common in the intermittent group (p < 0.001).

SCN5A "likely causative" variants showed a heterogeneous distribution (p = 0.02), increasing from non-diagnostic (2.0%) to spontaneous persistent (24.3%) patterns. Post-hoc analysis confirmed significance between these extremes (p = 0.0018), with a linear trend across ECG groups (p = 0.0024). Similar results were observed for LP/P variants alone (p = 0.041; trend p = 0.0046). No significant association emerged between SCN5A variants and other arrhythmic risk parameters (p > 0.05). In 210 NGS-tested patients, extending analysis to all genes confirmed the trend only for ion channel genes (p = 0.072), but not for structural or regulatory genes.

Conclusions

In BrS, "likely causative" and "causative" sodium channel variants but not structural or regulatory genes are associated with increasing ECG pattern severity, suggesting that ion channel genetics is a major determinant of the BrS phenotype. No other clinical or EP parameters, except palpitations and low-voltage areas, correlated with ECG expression.Distribution of SCN5A variants by ECG