AIMS: Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST 
segment elevation in V1-V3 ECG leads. Mutations SCN5A gene encoding for the 
cardiac voltage-gated Na(+) channel are found in some BrS patients, but also in 
family members with isolated conduction disturbances. However, some patients 
show coved ST elevation in the inferior or lateral leads whose association with 
SCN5A and familial conduction disturbances are poorly known.
METHODS AND RESULTS: Two novel SCN5A mutations, D1430N and Q1476X, were 
identified in two unrelated families comprising patients with Brugada-like ST 
elevation located in the inferior leads or isolated conduction disturbances. 
Wild-type (WT) and D1430N mutant channels were expressed in tsA201 cells. Patch 
clamp electrophysiological experiments revealed total absence of Na(+) current 
resulting from Nav1.5 mutant when compared to WT channels. Treatments known to 
restore trafficking defect (incubation at low temperature, with mexiletine or 
lidocaine) did not restore Na(+) current supporting that Nav1.5 mutation is not 
a defective trafficking mutation. Furthermore, immunocytolabelling indicates the 
membrane localisation of both WT and mutant channels confirming what we observed 
in our patch clamp experiments. This suggests that the mutation may induce a 
complete block of Na(+) permeation. The nonsense mutation Q1476X was leading to 
a premature stop codon and was not expressed.
CONCLUSION: Brugada-like ST elevation in the inferior ECG leads or isolated 
conduction disturbances were found in two unrelated families and associated with 
two novel SCN5A mutations. The missense and nonsense mutations are both 
resulting in a complete loss of ventricular Na(+) current explaining the 
phenotypes.