TY - JOUR
T1 - Spectrum and prevalence of mutations involving BrS1- Through BrS12-susceptibility genes in a cohort of unrelated patients referred for brugada syndrome genetic testing
T2 - Implications for genetic testing
AU - Crotti, Lia
AU - Marcou, Cherisse A.
AU - Tester, David J.
AU - Castelletti, Silvia
AU - Giudicessi, John R.
AU - Torchio, Margherita
AU - Medeiros-Domingo, Argelia
AU - Simone, Savastano
AU - Will, Melissa L.
AU - Dagradi, Federica
AU - Schwartz, Peter J.
AU - Ackerman, Michael J.
N1 - Funding Information:
To be considered a putative pathogenic mutation, the genetic variant had to be: 1) a nonsynonymous variant; and 2) absent in at least 700 ethnically matched controls (≥1,400 reference alleles) plus all available online databases, including the 1000 Human Genome Project database ( 23 ). Control genomic DNA was obtained from the European Collection of Cell Cultures (HPA Culture Collections, Salisbury, United Kingdom), the Human Genetic Cell Repository sponsored by the National Institute of General Medical Sciences and the Coriell Institute for Medical Research (Camden, New Jersey), and the Blood Transfusional Center at La Fondazione IRCCS Policlinico San Matteo di Pavia (Pavia, Italy).
PY - 2012/10/9
Y1 - 2012/10/9
N2 - 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 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.
AB - 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 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.
KW - Brugada syndrome
KW - ST-segment elevation
KW - cardiac arrest
KW - genetic testing
KW - ventricular arrhythmias
UR - http://www.scopus.com/inward/record.url?scp=84867081985&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867081985&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2012.04.037
DO - 10.1016/j.jacc.2012.04.037
M3 - Article
C2 - 22840528
AN - SCOPUS:84867081985
SN - 0735-1097
VL - 60
SP - 1410
EP - 1418
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 15
ER -