The phenotypic spectrum of TRPM4 variants: implications for conduction disease and arrhythmic risk

Background / Introduction

Cardiac conduction disorders (CCD) in young adults constitute an heterogeneous group of conditions characterized by impaired impulse initiation and propagation within the cardiac conduction system. Brugada syndrome (BrS) is an inherited arrhythmia disorder most frequently associated with loss-of-function mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel (Nav1.5). Although primarily recognized for its arrhythmic risk, BrS frequently encompasses conduction abnormalities, reflecting diffuse sodium channel dysfunction.

The TRPM4 gene encodes a calcium-activated, non-selective cation channel expressed in the specialized conduction tissue, where it modulates membrane depolarization and action potential dynamics. Pathogenic TRPM4 variants have been linked to a broad spectrum of conduction abnormalities and have also been described in patients with Brugada syndrome. Both gain-of-function and loss-of-function alterations ultimately reduce Nav1.5 channel availability, leading to a clinical phenotype that overlaps substantially with that of SCN5A mutation carriers.

Purpose

This study aims to characterize the clinical manifestations associated with TRPM4 variants, with particular focus on conduction disorders and Brugada syndrome.

Methods

We retrospectively analyzed a cohort of sixteen patients carrying TRPM4 variants. Clinical history, electrocardiographic findings, and the need for device implantation—including pacemakers and implantable cardioverter-defibrillators (ICDs)—were evaluated. The prevalence of CCD and BrS and their associated outcomes were quantified.

Results

Among the sixteen patients with TRPM4 variants, ten (62.5%) exhibited cardiac conduction disorders. Of these, 70% required pacemaker implantation before the age of 50, indicating early and clinically significant conduction system involvement. Six patients (37.5%) were diagnosed with Brugada syndrome, and 30% of them required ICD implantation due to documented arrhythmic events. Overall, TRPM4 variants were associated with a substantial burden of both conduction abnormalities and arrhythmia-related risk.

Conclusion

The findings of this study highlight the important role of TRPM4 variants in the pathogenesis of cardiac conduction disease and Brugada syndrome. These results underscore the value of including TRPM4 in genetic screening panels for patients with conduction disorders or suspected Brugada syndrome and support the need for further functional and longitudinal studies to better define the clinical course, molecular mechanisms, and therapeutic implications of TRPM4-associated cardiac disease.