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
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 SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb 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.
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 SCN5A-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.
Key Words
Brugada syndrome
cardiac arrest
genetic testing
ST-segment elevation
ventricular arrhythmias
Abbreviations and Acronyms
BrS
Brugada syndrome
CCS
Canadian Cardiovascular Society
CHRS
Canadian Heart Rhythm Society
ECG
electrocardiographic
EHRA
European Heart Rhythm Association
HRS
Heart Rhythm Society
SCD
sudden cardiac death
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Dr. Ackerman is a consultant for Biotronik, Boston Scientific, Medtronic, St. Jude Medical, Inc., and Transgenomic. Intellectual property derived from Dr. Ackerman's research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals, now recently acquired by Transgenomic). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Mr. Giudicessi was supported by a National Heart, Lung, and Blood Institute Kirschstein NRSA Individual Predoctoral MD/PhD Fellowship (F30-HL106993). The first 2 authors contributed equally to this work.