Electrocardiographic features associated with genetic positivity in brugada syndrome

Background

Brugada Syndrome (BrS) is an inherited channelopathy associated with an increased risk of sudden cardiac death (SCD). Genetic pathogenic variants are identified in less than half of cases and clinical predictors of its positivity are poorly defined.

Purpose

To assess whether routine electrocardiogram (ECG) identifies patients with non-spontaneous BrS, more likely to have positive genetic testing.

Methods

Retrospective, single-center observational study including 227 patients with non-spontaneous BrS, between 2014 and 2025. Basal ECG was obtained in all patients. Patients with inconclusive genetic results were excluded from the analysis. Clinical characteristics and ECG parameters were compared between patients with positive (+) and negative (-) genetic testing. Multivariable logistic regression using a forward likelihood ratio method was performed to identify independent ECG predictors of genetic positivity.

Results

A total of 110 patients met the inclusion criteria, of whom 49 (44.5%) tested (+). Mean age was 48.9±14.4 years, and 44 patients (40.0%) were female and 59 (53.6%) were index cases. Patients with (+) genetics were younger at diagnosis (45.2±15.7 vs. 51.9±12.6years, p=0.014) and more often female (51.0% vs. 31.1%, p=0.034). Previous symptoms and family history of SCD were similar between groups. There were no differences in device implantation rates, nor in cardiovascular events during follow-up (mean 711.9±298.8months).

First-degree atrioventricular block was significantly more common in the (+) group (28.6% vs. 4.9%, p<0.001), while no differences were observed in intraventricular conduction disturbances. Several ECG parameters differed between groups, including longer PR interval, more rightward QRS axis, lower R-wave amplitude in lead DI and aVR, and higher S-wave amplitude in aVL (all p<0.05) in (+) genetics.

In multivariable analysis, longer PR interval (OR 1.034 per ms [1.02–1.05], p<0.001), QRS axis (OR 1.015 per degree [1.00–1.03], p=0.035), and S wave in aVL (OR 25.23 per mV [1.11–571.82], p=0.043) were independently associated with (+) genetic testing, whereas R wave in lead aVR was strongly negatively associated (OR 0.904 per 0.01mV [0.83-0.98], p=0.019).

ROC curve analysis demonstrated that the PR interval (AUC=0.71; optimal cut-off=185ms, sensitivity=52.1%, specificity=85.2%), QRS axis (AUC=0.70; optimal cut-off=60°, sensitivity=51.1%, specificity=90.2%), and S-wave in aVL (AUC=0.68; optimal cut-off=0.04mV, sensitivity=74.5%, specificity=57.4%) were all statistically significant predictors of genetic test positivity (all p<0.05).

Conclusions

In patients with BrS, genetic test (+) is associated with distinct ECG conduction features, particularly PR prolongation and specific frontal plane voltage patterns, while clinical presentation and outcomes remain similar. These findings suggest that surface ECG parameters may aid in identifying patients with a higher likelihood of underlying pathogenic variants.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.