Abstract

Introduction Risk stratification of patients with the SCN5A-E1784K mutation is challenging because they can express Brugada syndrome, long QT syndrome (LQTS), or both phenotypes (overlap syndrome). This study compared arrhythmic risk in patients with overlap syndrome versus single phenotype presentations.

Methods We retrospectively enrolled patients aged 12 and older carrying the SCN5A-E1784K mutation. The primary outcome was major cardiac events (MCEs) defined as sustained ventricular arrhythmia, cardiopulmonary arrest and sudden cardiac death. Comparisons were made between patients expressing single phenotype (Brugada syndrome or LQTS type 3) and overlap syndrome.

Results Forty-seven patients were enrolled (32 overlap group, 15 single phenotype group). MCE occurrence was 25% (8/32) in the overlap group and 6.7% (1/15) in the single phenotype group. Median follow-up was 156 months (single phenotype) and 127 months (overlap group). Despite a trend toward higher risk, comparison showed no statistically significant difference (OR 4.67, 95% CI: 0.53-41.4, p=0.275). Ajmaline testing reclassified 12% of patients, highlighting the importance of comprehensive diagnostic evaluation.

Conclusion This study describes the largest cohort of SCN5A-E1784K mutation carriers reported. Although not statistically significant due to event rarity and sample size, results reveal a clear trend toward higher MCE prevalence in the overlap group. Ajmaline testing revealed underdiagnosis of overlap syndrome. Larger studies are needed for definitive conclusions.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT05274646

Funding Statement

None

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Institutional Review Board of CHRU Saint Jacques in Besançon, France (ethics approval number: 2021-A03006-35)

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

Emails: 40009074co.univ-reunion.fr, rene.bunchu-reunion.fr, olivier.geoffroychu-reunion.fr, pierre.roumegouchu-reunion.fr, frederique.payetchu-reunion.fr, francois.wiartchu-reunion.fr, gael.clericichu-reunion.fr, josselin.duchateauchu-bordeaux.fr, maxime.churetchu-reunion.fr

Conflict of Interest Statement: The authors declare no conflicts of interest.

Funding: None

Data Availability Statement: The data that support the findings of this study are available upon request from the participating institutions, in compliance with patient privacy regulations.

Clinical Trial Disclosure: NCT05274646

Ethical Disclosure: This study was approved by the Institutional Review Board of CHRU Saint Jacques in Besançon, France (ethics approval number: 2021-A03006-35)

Data Availability

The data that support the findings of this study are available upon request from the participating institutions, in compliance with patient privacy regulations.

AbreviationsBrSbrugada syndromeCIconfidence intervalECGelectrocardiogramMCEmajor cardiac eventORodds ratioLQTSlong QT syndrome