Spectrum and Prewaieice of Mutations Involving. BrS1- Through BiS12-SusceptibilHy: Genes in a Color! of Unrelated Patients leferred for Brigada Syndrome Genetic Testing Implications for Genetic Testing

摘要

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.BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V_1 to V_3; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events.Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrSl- 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).Overall, 27 patients (21%) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCNIBb mutation, and an HCN4 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.We identified1 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 SCN5A-mediated BrS (BrSl) when the PQ interval exceeds 200 ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval.