NovelSCN5AMutation Leading Either to Isolated Cardiac Conduction Defect or Brugada Syndrome in a Large French Family

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Abstract
Background— TheSCN5Agene encoding the human cardiac sodium channel α subunit plays a key role in cardiac electrophysiology. Mutations inSCN5Alead 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 singleSCN5Amissense 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 G1406RSCN5Amutation. 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-mutatedSCN5Ashowed no detectable Na+current but normal protein trafficking. Conclusions— We conclude that the same mutation in theSCN5Agene 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 aSCN5Amutation.