Clinical profile and prognosis of brugada syndrome SCN5A variant carriers with negative sodium channel blocker challenge.

AIMS: Loss-of-function (LOF) variants in SCN5A are associated with Brugada syndrome (BrS), progressive conduction slowing, and other arrhythmias. While the prognosis of SCN5A carriers with a positive sodium channel blocker challenge (SCBC) is established, data on those with negative SCBC are limited.

OBJECTIVE

To assess the clinical presentation and prognosis of SCN5A variant carriers with negative SCBC, and compare them to relatives with positive SCBC.

METHODS AND

RESULTS

We retrospectively included patients from five university hospitals (2000-2024) carrying a pathogenic or likely pathogenic SCN5A variant and negative SCBC. Relatives with the same variant and positive SCBC were also analysed. Patients with spontaneous type 1 ECG, gain-of-function variants, double variants, or ACMG class 1-3 variants were excluded. Clinical, ECG, genetic, and follow-up data were collected. Conduction slowing was evaluated using the PR interval and QRS duration. The cohort included 162 patients from 43 families (median age 37 ± 19 years, 46% male), of whom 69 (43%) had negative SCBC. Among these 69 patients, 25 (36%) had baseline intraventricular conduction defects, and 19 (28%) had first-degree AV block. After a median follow-up of 75 [40-168] months, 52% of patients developed progressive conduction slowing. Negative SCBC patients had fewer conduction defects (36% vs. 70%, p = 0.002) and ICD implantations (1% vs. 23%, P < 0.001). Non-missense variants were associated with more conduction slowing (71% vs. 42%, P = 0.04).

CONCLUSION

This multicentre study provides the largest analysis of SCN5A carriers with negative SCBC, showing excellent arrhythmic prognosis despite frequent progressive conduction slowing.