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Michael J Ackerman - One of the best experts on this subject based on the ideXlab platform.
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mexiletine shortens the qt interval in patients with potassium channel mediated type 2 long qt syndrome
Circulation-arrhythmia and Electrophysiology, 2019Co-Authors: Martijn J Bos, Peter J Schwartz, Lia Crotti, Federica Dagradi, Ram K Rohatgi, Silvia Castelletti, Michael J AckermanAbstract:Background: Long QT syndrome is a potentially lethal yet highly treatable Cardiac Channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel bl...
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Special Article Confirmation of Cause and Manner of Death Via a Comprehensive Cardiac Autopsy Including Whole Exome Next-Generation Sequencing
2016Co-Authors: Christina G. Loporcaro, Michael J AckermanAbstract:Annually, the sudden death of thousands of young people remains inadequately explained despite medicolegal inves-tigation. Postmortem genetic testing for channelopathies/ cardiomyopathies may illuminate a potential Cardiac mechanism and establish a more accurate cause and manner of death and provide an actionable genetic marker to test surviving family members who may be at risk for a fatal arrhythmia. Whole exome sequencing allows for simultaneous genetic interrogation of an individual’s entire estimated library of approximately 30 000 genes. Follow-ing an inconclusive autopsy, whole exome sequencing and gene-specific surveillance of all known major Cardiac Channelopathy/cardiomyopathy genes (90 total) were performed on autopsy blood–derived genomic DNA from a previously healthy 16-year-old adolescent female found deceased in her bedroom. Whole exome sequencing analysis revealed a R249Q-MYH7 mutation associated previously with familial hypertrophic cardiomyopathy, sudden death, and impaired b–myosin heavy chain (MHC-b) actin-translocating and actin-activated ATPase (adenosine triphosphatase) activity. Whole exome se-quencing may be an efficient and cost-effective approach to incorporate molecular studies into the conventional postmortem examination
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eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities task force 10 the Cardiac channelopathies a scientific statement from the american heart association and american college of cardiology
Circulation, 2015Co-Authors: Michael J Ackerman, Douglas P Zipes, Richard J Kovacs, Barry J MaronAbstract:The Cardiac channelopathies are a collection of primary, genetically mediated heart rhythm disorders (also referred to as the primary electrical disorders) that are generally associated with a structurally normal heart and a propensity for syncope, seizures, or sudden Cardiac arrest precipitated by a Channelopathy-mediated episode of nonsustained or sustained polymorphic ventricular tachycardia (torsade de pointes) or ventricular fibrillation. These Cardiac channelopathies include long-QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), early repolarization syndrome, short-QT syndrome, and potentially idiopathic ventricular fibrillation. Approximately 1 in 1000 people are affected by a Cardiac Channelopathy, with LQTS being most common, involving an estimated 1 in 2000 people.1 Presently, these channelopathies should be viewed as potentially lethal but highly treatable conditions. However, unlike the various bradyarrhythmias and tachyarrhythmias detailed in the Task Force 9 report,2 there remains significant variability and heterogeneity among pediatric and adult heart rhythm specialists in terms of their ability to diagnose, risk stratify, and treat patients with these conditions. For example, in 1 study, 40% of the patients who received a second opinion evaluation at a LQTS specialty center for a previously rendered diagnosis of LQTS by a heart rhythm specialist were reclassified as otherwise normal, having insufficient evidence to merit that diagnostic consideration.3 This is explained in part by the advanced knowledge and training required to evaluate and treat these less common channelopathies. Accordingly, any return-to-play decision for an athlete suspected of having a Cardiac Channelopathy necessitates that the athlete be evaluated, risk stratified, treated, and counseled by a heart rhythm specialist or genetic cardiologist with sufficient experience and expertise in these syndromes.4 For the most part, restriction from virtually all competitive sports has been the guideline-based recommendation since 2005 for athletes with a Cardiac Channelopathy, regardless of the underlying Channelopathy.5, …
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automated external defibrillator rescues among children with diagnosed and treated long qt syndrome
Heart Rhythm, 2015Co-Authors: Kavitha N Pundi, Bryan C Cannon, Michael J AckermanAbstract:Background Long QT syndrome (LQTS) is a potentially lethal yet highly treatable Cardiac Channelopathy. A comprehensive LQTS-directed treatment program often includes an automated external defibrillator (AED). Objective The purpose of this study was to determine the incidence of AED rescues among children evaluated, risk-stratified, and treated in an LQTS specialty center. Methods We performed a retrospective review of the electronic medical records to identify 1665 patients evaluated in our Genetic Heart Rhythm Clinic (1999–2013). Subset analysis was performed on 291 children managed without an implantable cardioverter-defibrillator (ICD). Results The average age at diagnosis was 8.3 ± 5.7 years with an average. QTc of 463 ± 40 ms (17% ≥500 ms). The represented LQTS genotypes included type 1 (LQT1) in 52%, type 2 (LQT2) in 35%, and type 3 (LQT3) in 7%. During follow-up, 3 of 291 children (1%) had a Cardiac arrest with an appropriate AED rescue (2/51 symptomatic, 1/240 asymptomatic). The first AED rescue occurred during exercise in a symptomatic 3-year-old boy with compound LQT1 treated with beta-blocker and videoscopic left Cardiac sympathetic denervation (LCSD). The second AED rescue occurred in a remotely symptomatic 14-year-old boy with high-risk LQT2 (QTc >550 ms) on a beta-blocker who previously declined a prophylactic ICD. The third AED rescue involved an asymptomatic 17-year-old girl with LQT3 on mexiletine who collapsed in school. Conclusion An AED should seldom be necessary in an appropriately treated child with LQTS. Nevertheless, despite only 3 AED rescues in more than 1700 patient-years, an AED can be a lifesaving and cost-effective part of an LQTS patient's comprehensive sudden death prevention program.
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exome sequencing and systems biology converge to identify novel mutations in the l type calcium channel cacna1c linked to autosomal dominant long qt syndrome
Circulation-cardiovascular Genetics, 2013Co-Authors: Nicole J. Boczek, David J Tester, Sumit Middha, Jabe M Best, John R Giudicessi, Jared M Evans, Timothy J Kamp, Michael J AckermanAbstract:Background— Long QT syndrome (LQTS) is the most common Cardiac Channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results— We combined whole-exome sequencing and bioinformatic/systems biology to identify the pathogenic substrate responsible for nonsyndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree, and we established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with “genotype-negative/phenotype-positive” LQTS. Whole-exome sequencing was used on 3 members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, cosegregated with the disease within the pedigree, was ranked by 3 disease-network algorithms as the most probable LQTS-susceptibility gene and involves a conserved residue localizing to the proline, gltamic acid, serine, and threonine (PEST) domain in the II-III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain of function with increased I Ca,L and increased surface membrane expression of the channel compared to wild type. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Ca v 1.2’s PEST domain. Conclusions— This study provides evidence that coupling whole-exome sequencing and bioinformatic/systems biology is an effective strategy for the identification of potential disease-causing genes/mutations. The identification of a functional CACNA1C mutation cosegregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.
David J Tester - One of the best experts on this subject based on the ideXlab platform.
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exome sequencing and systems biology converge to identify novel mutations in the l type calcium channel cacna1c linked to autosomal dominant long qt syndrome
Circulation-cardiovascular Genetics, 2013Co-Authors: Nicole J. Boczek, David J Tester, Sumit Middha, Jabe M Best, John R Giudicessi, Jared M Evans, Timothy J Kamp, Michael J AckermanAbstract:Background— Long QT syndrome (LQTS) is the most common Cardiac Channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results— We combined whole-exome sequencing and bioinformatic/systems biology to identify the pathogenic substrate responsible for nonsyndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree, and we established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with “genotype-negative/phenotype-positive” LQTS. Whole-exome sequencing was used on 3 members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, cosegregated with the disease within the pedigree, was ranked by 3 disease-network algorithms as the most probable LQTS-susceptibility gene and involves a conserved residue localizing to the proline, gltamic acid, serine, and threonine (PEST) domain in the II-III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain of function with increased I Ca,L and increased surface membrane expression of the channel compared to wild type. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Ca v 1.2’s PEST domain. Conclusions— This study provides evidence that coupling whole-exome sequencing and bioinformatic/systems biology is an effective strategy for the identification of potential disease-causing genes/mutations. The identification of a functional CACNA1C mutation cosegregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.
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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
Journal of the American College of Cardiology, 2009Co-Authors: Argelia Medeirosdomingo, David J Tester, Arthur A.m. Wilde, Zahurul A Bhuiyan, Nynke Hofman, Hennie Bikker, Peter J Van Tintelen, Marcel M A M Mannens, Michael J AckermanAbstract: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 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 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.
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spectrum and prevalence of mutations from the first 2 500 consecutive unrelated patients referred for the familion long qt syndrome genetic test
Heart Rhythm, 2009Co-Authors: Jamie D Kapplinger, David J Tester, Arthur A.m. Wilde, Benjamin A Salisbury, Janet L Carr, Carole Harriskerr, Guido D Pollevick, Michael J AckermanAbstract:Background Long QT syndrome (LQTS) is a potentially lethal, highly treatable Cardiac Channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation. Objectives Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION ® LQTS clinical genetic test. Methods Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 ± 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). Results Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in ≥1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1 , 159 of 226 in KCNH2 , and 70 of 110 in SCN5A . Conclusion This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results.
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postmortem genetic testing for conventional autopsy negative sudden unexplained death an evaluation of different dna extraction protocols and the feasibility of mutational analysis from archival paraffin embedded heart tissue
American Journal of Clinical Pathology, 2008Co-Authors: Elisa Carturan, David J Tester, Brian C Brost, Cristina Basso, Gaetano Thiene, Michael J AckermanAbstract:One third of autopsy-negative sudden unexplained deaths (SUDs) can be attributed to a Cardiac Channelopathy. Typically, paraffin-embedded tissue (PET) is the only source of DNA available for genetic analyses. We examined different DNA extraction procedures, involving 2 deparaffinization methods, 2 digestion methods, 4 laboratory-based purification methods, and 5 commercial kits. Mutational analysis involving 25 RYR2 exons was performed on PET DNA from 35 SUD cases to evaluate the feasibility of using PET DNA for genetic testing. With the best PET-DNA extraction method, an average of only two thirds of the region of interest could be evaluated. Although we initially identified 5 missense mutations in 5 of 35 SUD cases, repeated analysis failed to confirm these mutations. DNA from PET should be considered error prone and unreliable in comprehensive surveillance of SUD-associated genes. Given these shortcomings, the standard autopsy for SUD should include archiving EDTA-preserved blood or frozen tissue to facilitate postmortem genetic testing.
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diagnostic miscues in congenital long qt syndrome
Circulation, 2007Co-Authors: Nathaniel W Taggart, Carla M Haglund, David J Tester, Michael J AckermanAbstract:Background— Long-QT syndrome (LQTS) is a potentially lethal Cardiac Channelopathy that can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. Because of increased physician and public awareness of warning signs suggestive of LQTS, there is the potential for LQTS to be overdiagnosed. We sought to determine the agreement between the dismissal diagnosis from an LQTS subspecialty clinic and the original referral diagnosis. Methods and Results— Data from the medical record were compared with data from the outside evaluation for 176 consecutive patients (121 females, median age 16 years, average referral corrected QT interval [QTc] of 481 ms) referred with a diagnosis of LQTS. After evaluation at Mayo Clinic’s LQTS Clinic, patients were categorized as having definite LQTS (D-LQTS), possible LQTS (P-LQTS), or no LQTS (No-LQTS). Seventy-three patients (41%) were categorized as No-LQTS, 56 (32%) as P-LQTS, and only 47 (27%) as D-LQTS. The yield of genetic testing among D-LQTS patients was 78% co...
Stuart A Cook - One of the best experts on this subject based on the ideXlab platform.
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Characterization of a novel KCNQ1 mutation for type 1 long QT syndrome and assessment of the therapeutic potential of a novel IKs activator using patient-specific induced pluripotent stem cell-derived cardiomyocytes
Stem Cell Research & Therapy, 2015Co-Authors: Heming Wei, Dou Huang, Zhenfeng Liu, Li Jun Loh, Omedul Islam, Reginald Liew, Winston Shim, Stuart A CookAbstract:Introduction Type 1 long QT syndrome (LQT1) is a common type of Cardiac Channelopathy associated with loss-of-function mutations of KCNQ1 . Currently there is a lack of drugs that target the defected slowly activating delayed rectifier potassium channel (IKs) . With LQT1 patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs), we tested the effects of a selective IKs activator ML277 on reversing the disease phenotypes. Methods A LQT1 family with a novel heterozygous exon 7 deletion in the KCNQ1 gene was identified. Dermal fibroblasts from the proband and her healthy father were reprogrammed to hiPSCs and subsequently differentiated into hiPSC-CMs. Results Compared with the control, LQT1 patient hiPSC-CMs showed reduced levels of wild type KCNQ1 mRNA accompanied by multiple exon skipping mRNAs and a ~50% reduction of the full length Kv7.1 protein. Patient hiPSC-CMs showed reduced IKs current (tail current density at 30 mV: 0.33 ± 0.02 vs. 0.92 ± 0.21, P
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characterization of a novel kcnq1 mutation for type 1 long qt syndrome and assessment of the therapeutic potential of a novel iks activator using patient specific induced pluripotent stem cell derived cardiomyocytes
Stem Cell Research & Therapy, 2015Co-Authors: Jun Lu, Dou Huang, Omedul Islam, Reginald Liew, Winston Shim, Stuart A CookAbstract:Type 1 long QT syndrome (LQT1) is a common type of Cardiac Channelopathy associated with loss-of-function mutations of KCNQ1. Currently there is a lack of drugs that target the defected slowly activating delayed rectifier potassium channel (IKs). With LQT1 patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs), we tested the effects of a selective IKs activator ML277 on reversing the disease phenotypes. A LQT1 family with a novel heterozygous exon 7 deletion in the KCNQ1 gene was identified. Dermal fibroblasts from the proband and her healthy father were reprogrammed to hiPSCs and subsequently differentiated into hiPSC-CMs. Compared with the control, LQT1 patient hiPSC-CMs showed reduced levels of wild type KCNQ1 mRNA accompanied by multiple exon skipping mRNAs and a ~50% reduction of the full length Kv7.1 protein. Patient hiPSC-CMs showed reduced IKs current (tail current density at 30 mV: 0.33 ± 0.02 vs. 0.92 ± 0.21, P < 0.05) and prolonged action potential duration (APD) (APD 50 and APD90: 603.9 ± 39.2 vs. 319.3 ± 13.8 ms, P < 0.005; and 671.0 ± 41.1 vs. 372.9 ± 14.2 ms, P < 0.005). ML277, a small molecule recently identified to selectively activate KV7.1, reversed the decreased IKs and partially restored APDs in patient hiPSC-CMs. From a LQT1 patient carrying a novel heterozygous exon7 deletion mutation of KCNQ1, we generated hiPSC-CMs that faithfully recapitulated the LQT1 phenotypes that are likely associated with haploinsufficiency and trafficking defect of KCNQ1/Kv7.1. The small molecule ML277 restored IKs function in hiPSC-CMs and could have therapeutic value for LQT1 patients.
Arthur A.m. Wilde - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of the American College of Cardiology, 2009Co-Authors: Argelia Medeirosdomingo, David J Tester, Arthur A.m. Wilde, Zahurul A Bhuiyan, Nynke Hofman, Hennie Bikker, Peter J Van Tintelen, Marcel M A M Mannens, Michael J AckermanAbstract: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 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 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.
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spectrum and prevalence of mutations from the first 2 500 consecutive unrelated patients referred for the familion long qt syndrome genetic test
Heart Rhythm, 2009Co-Authors: Jamie D Kapplinger, David J Tester, Arthur A.m. Wilde, Benjamin A Salisbury, Janet L Carr, Carole Harriskerr, Guido D Pollevick, Michael J AckermanAbstract:Background Long QT syndrome (LQTS) is a potentially lethal, highly treatable Cardiac Channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation. Objectives Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION ® LQTS clinical genetic test. Methods Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 ± 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). Results Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in ≥1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1 , 159 of 226 in KCNH2 , and 70 of 110 in SCN5A . Conclusion This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results.
Argelia Medeirosdomingo - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of the American College of Cardiology, 2009Co-Authors: Argelia Medeirosdomingo, David J Tester, Arthur A.m. Wilde, Zahurul A Bhuiyan, Nynke Hofman, Hennie Bikker, Peter J Van Tintelen, Marcel M A M Mannens, Michael J AckermanAbstract: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 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 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.