Abstract
Brugada syndrome is an inherited arrhythmogenic disorder leading to sudden death predominantly in the 3–4 decade. To date the only reliable treatment is the implantation of a cardioverter defibrillator; however, better criteria for risk stratification are needed, especially for asymptomatic subjects. Brugada syndrome genetic bases have been only partially understood, accounting for <30% of patients, and have been poorly correlated with prognosis, preventing inclusion of genetic data in current guidelines. We designed an observational study to identify genetic markers for risk stratification of Brugada patients by exploratory statistical analysis. The presence of genetic variants, identified by SCN5A gene analysis and genotyping of 73 candidate polymorphisms, was correlated with the occurrence of major arrhythmic events in a cohort of 92 Brugada patients by allelic association and survival analysis. In all, 18 mutations were identified in the SCN5A gene, including 5 novel, and statistical analysis indicated that mutation carriers had a significantly increased risk of major arrhythmic events (P=0.024). In addition, we established association of five polymorphisms with major arrhythmic events occurrence and consequently elaborated a pilot risk stratification algorithm by calculating a weighted genetic risk score, including the associated polymorphisms and the presence of SCN5A mutation as function of their odds ratio. This study correlates for the first time the presence of genetic variants with increased arrhythmic risk in Brugada patients, representing a first step towards the design of a new risk stratification model.
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Acknowledgements
We are grateful to all the patients and their families. We acknowledge all personnel of the Arrhythmology Unit of San Raffaele Hospital, in particular, Francesco Sacco and Francesca Zuffada for collaboration in BrS patients’ characterization and Vincenzo Santinelli for critically revising the manuscript. We also thank Dr Amarild Cuko, Dr Ciro Indolfi, Dr Massimo Zoni Berisso, Dr Stefano Favale and Dr Luca Rocchetti for collaboration in identifying patients. We thank Alessandra Foglio and Chiara Redaelli for help in SCN5A genetic analysis and setup of SNP genotyping. This study was supported by grants from Medtronic Italy (to MF) and Italian Istituto Superiore di Sanità (ISS-526D/55 to CP).
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Sommariva, E., Pappone, C., Martinelli Boneschi, F. et al. Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification. Eur J Hum Genet 21, 911–917 (2013). https://doi.org/10.1038/ejhg.2012.289
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DOI: https://doi.org/10.1038/ejhg.2012.289
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