BACKGROUND: The SCN5A gene encoding the human cardiac sodium channel alpha 
subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead 
to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, 
and isolated progressive cardiac conduction defect (Lenègre disease).
METHODS AND RESULTS: In the present study, we report the identification of a 
novel single SCN5A missense mutation causing either Brugada syndrome or an 
isolated cardiac conduction defect in the same family. A G-to-T mutation at 
position 4372 was identified by direct sequencing and was predicted to change a 
glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the 
sodium channel protein. Among 45 family members, 13 were carrying the G1406R 
SCN5A mutation. Four individuals from 2 family collateral branches showed 
typical Brugada phenotypes, including ST-segment elevation in the right 
precordial leads and right bundle branch block. One symptomatic patient with the 
Brugada phenotype required implantation of a cardioverter-defibrillator. Seven 
individuals from 3 other family collateral branches had isolated cardiac 
conduction defects but no Brugada phenotype. Three flecainide test were 
negative. One patient with an isolated cardiac conduction defect had an episode 
of syncope and required pacemaker implantation. An expression study of the 
G1406R-mutated SCN5A showed no detectable Na(+) current but normal protein 
trafficking.
CONCLUSIONS: We conclude that the same mutation in the SCN5A gene can lead 
either to Brugada syndrome or to an isolated cardiac conduction defect. Our 
findings suggest that modifier gene(s) may influence the phenotypic consequences 
of a SCN5A mutation.