Spectrum and Prevalence of Mutations Involving BrS1- Through BrS12-Susceptibility Genes in a Cohort of Unrelated Patients Referred for Brugada Syndrome Genetic Testing: Implications for Genetic Testing

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• 作者：Lia Crotti ; Cherisse A. Marcou ; David J. Tester ; Silvia Castelletti ; John R. Giudicessi ; Margherita Torchio ; Argelia Medeiros-Domingo ; Savastano Simone ; Melissa L. Will ; Federica Dagradi ; Peter J. Schwartz ; Michael J. Ackerman
• 关键词：Brugada syndrome ; cardiac arrest ; genetic testing ; ST-segment elevation ; ventricular arrhythmias
• 刊名：Journal of the American College of Cardiology
• 出版年：2012
• 出版时间：9 October, 2012
• 年：2012
• 卷：60
• 期：15
• 页码：1410-1418
• 全文大小：974 K

文摘

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Objectives

The aim of this study was to provide the spectrum and prevalence of mutations in the 12 Brugada syndrome (BrS)-susceptibility genes discovered to date in a single large cohort of unrelated BrS patients.

Background

BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V₁ to V₃; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events.

Methods

Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrS1- through BrS12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only).

Results

Overall, 27 patients (21 % ) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an m>SCN5Am> mutation, 2 with a m>CACNB2Bm> mutation, and 1 each with a m>KCNJ8m> mutation, a m>KCND3m> mutation, an m>SCN1Bbm> mutation, and an m>HCN4m> mutation. The overall mutation yield was 23 % in the type 1 BrS ECG pattern-only patients versus 17 % in the clinically diagnosed BrS patients and was significantly greater among young men <20 years of age with clinically diagnosed BrS and among patients who had a prolonged PQ interval.

Conclusions

We identified putative pathogenic mutations in ¡«20 % of our BrS cohort, with BrS genes 2 through 12 accounting for <5 % . Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40 % for m>SCN5A-m>mediated BrS (BrS1) when the PQ interval exceeds 200 ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval.