Published Online
on September 29, 2009

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Original Article

SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome

Vincent Probst^1,10; Arthur A.M. Wilde²; Julien Barc³; Frederic Sacher⁴; Dominique Babuty⁵; Philippe Mabo⁶; Jacques Mansourati⁷; Solena Le Scouarnec³; Florence Kyndt¹; Cedric Le Caignec⁸; Pascale Guicheney⁹; Laetitia Gouas⁹; Juliette Albuisson⁸; Paola G. Meregalli²; Hervé Le Marec¹; Hanno L. Tan² and Jean-Jacques Schott¹

¹ INCERM & CNRS & Univ. de Nantes & CHU de Nantes, Nantes, France;
² Academic Medical Center, University of Amsterdam, the Netherlands;
³ INCERM & CNRS & Univ. de Nantes, Nantes, France;
⁴ Hôpital cardiologique du Haut Leveque, Bordeaux, France;
⁵ Hôpital Trousseau, Tours, France;
⁶ Hôpital Pontchaillou, Rennes, France;
⁷ Centre Hospitalo-Universitaire de Brest, Brest, France;
⁸ CHU de Nantes, Nantes, France;
⁹ INSERM, Paris, France

^* Corresponding author; email: vincent.probst{at}chu-nantes.fr

Background—Mutations in SCN5A are identified in about 20-30% of probands affected by Brugada syndrome (BrS). However, in familial studies the relationship between SCN5A mutations and BrS remains poorly known. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families.

Methods and Results—Families were included if at least 5 family members were carriers of the SCN5A mutation identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+) (47%). In 5 families, we found 8 individuals affected by BrS, but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, while 5 had a type I ECG only after administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than non-carriers, demonstrating that these mutations exerted functional effects.

Conclusions—Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels.

Key Words: arrhythmia • death, sudden (if surviving, use heart arrest) • genetics • tachyarrhythmias • Brugada syndrome • SCN5A