TY - JOUR
T1 - The RYR2-Encoded Ryanodine Receptor/Calcium Release Channel in Patients Diagnosed Previously With Either Catecholaminergic Polymorphic Ventricular Tachycardia or Genotype Negative, Exercise-Induced Long QT Syndrome. A Comprehensive Open Reading Frame Mutational Analysis
AU - Medeiros-Domingo, Argelia
AU - Bhuiyan, Zahurul A.
AU - Tester, David J.
AU - Hofman, Nynke
AU - Bikker, Hennie
AU - van Tintelen, J. Peter
AU - Mannens, Marcel M.A.M.
AU - Wilde, Arthur A.M.
AU - Ackerman, Michael J.
N1 - Funding Information:
Comprehensive open reading frame/splice site mutational analysis of all 105 RYR2 exons was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing as described previously ( 11 ). The flanking primers used for polymerase chain reaction were published previously or designed with Oligo software (Molecular Biology Insights, Cascade, Colorado) and are available on request. We also searched for large genomic rearrangements affecting exon 3, as reported previously ( 12 ). All putative pathogenic variants must have been absent in 400 reference alleles (100 healthy Caucasian and 100 healthy black) obtained from the Human Genetic Cell Repository sponsored by the National Institute of General Medical Sciences and the Coriell Institute for Medical Research (Camden, New Jersey) to be considered as potentially disease related.
PY - 2009/11/24
Y1 - 2009/11/24
N2 - Objectives: This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc). Background: Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. Methods: Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 ± 15 years, mean QTc 428 ± 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45). Results: Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons. Conclusions: Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that ≈65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.
AB - Objectives: This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc). Background: Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. Methods: Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 ± 15 years, mean QTc 428 ± 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45). Results: Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons. Conclusions: Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that ≈65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.
KW - catecholaminergic polymorphic ventricular tachycardia
KW - exertional syncope
KW - ryanodine receptor
KW - sudden cardiac death
UR - http://www.scopus.com/inward/record.url?scp=71849090068&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=71849090068&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2009.08.022
DO - 10.1016/j.jacc.2009.08.022
M3 - Article
C2 - 19926015
AN - SCOPUS:71849090068
SN - 0735-1097
VL - 54
SP - 2065
EP - 2074
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 22
ER -