Background: Transient receptor potential melastatin member 4 ( TRPM 4) is a nonselective cation channel. TRPM 4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM 4‐dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM 4 genetic variants found in patients with congenital or childhood atrioventricular block. Methods and Results: Ninety‐one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare TRPM 4 genetic variants were identified and investigated. The variants were expressed heterologously in HEK 293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole‐cell patch‐clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered SUMO ylation of TRPM 4 may cause a gain of function; however, we did not find any evidence that supports SUMO ylation as being directly involved for the gain‐of‐function variant. Conclusions: This study underpins the role of TRPM 4 in the cardiac conduction system. The loss‐of‐function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding‐dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.

Background—: Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family. Methods and Results—: A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Na _v 1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells. Conclusions—: Gain-of-function of Na _v 1.5 may cause familial forms of exercise-induced polymorphic ventricular arrhythmias.