Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A:.
BACKGROUND
Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V(1) to V(3) of patients with structurally normal hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in SCN5A.


RESULTS
We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in SCN5A. The R367H mutation failed to generate any current when heterologously expressed in HEK cells.


CONCLUSIONS
Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false-positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome.
Hong
Kui
K
Molecular Genetics Program, Masonic Medical Research Laboratory, Utica, New York 13501, USA. brugada@mmrl.edu
Berruezo-Sanchez
Antonio
A
Poungvarin
Naravat
N
Oliva
Antonio
A
Vatta
Matteo
M
Brugada
Josep
J
Brugada
Pedro
P
Towbin
Jeffrey A
JA
Dumaine
Robert
R
Piñero-Galvez
Carlos
C
Antzelevitch
Charles
C
Brugada
Ramon
R
D000328:Adult; D000404:Ajmaline; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D002037:Bundle-Branch Block / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D015897:Comorbidity; D003645:Death, Sudden / Q000453:epidemiology*; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D010641:Phenotype; D017678:Sex Distribution; D015222:Sodium Channels / Q000235:genetics*; D013030:Spain / Q000453:epidemiology; D013577:Syndrome
D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D000404:Ajmaline