Nav1.5/R1193Q polymorphism is associated with both long QT and Brugada syndromes

Brugada syndrome (BS) and long QT syndrome (LQTS) are electrical disorders with a genetic background. They are revealed on surface electrocardiograms as either right bundle branch block and ST segment elevation in the right pericardial leads (V1, V2 and V3) in BS or as a long QTc interval on all 12 leads of the electrocardiogram in LQTS. Both BS and LQTS can lead to syncope and even sudden death. The R1193Q SCN5A variant was recently associated with LQTS, BS and cardiac conductance disease.

The aim of the present study was to screen the SCN5A gene from two patients -- one with BS and the other showing signs of a BS/LQTS phenotype -- for mutations, and to characterize the effect of the mutations on channel function using the patch clamp technique.

A heterozygous mutation (R1193Q) was identified on the SCN5A gene in both patients. The R1193Q polymorphism was absent in 100 unrelated control alleles, suggesting that it has a low frequency in the French Canadian population. Mutant R1193Q expressed in tsA201 cells, which was studied using the patch clamp technique, had a persistent sodium current that could account for the QTc prolongation. A shift of steady-state inactivation toward more hyperpolarized voltages was observed that could explain the BS phenotype.

The R1193Q polymorphism is definitively associated with cardiac electrical abnormalities.