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QUARTERLY FOCUS ISSUE: HEART RHYTHM DISORDERS

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

Argelia Medeiros-Domingo, MD, PhD^_*, Zahurul A. Bhuiyan, MD, PhD, David J. Tester, BS^_*, Nynke Hofman, MSc, Hennie Bikker, PhD, J. Peter van Tintelen, MD, PhD^¶, Marcel M.A.M. Mannens, PhD, Arthur A.M. Wilde, MD, PhD^,|| and Michael J. Ackerman, MD, PhD^_*,,,_*

^_* Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
^|| Department of Cardiology and Heart Failure Research Centre, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
^¶ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

Manuscript received May 5, 2009; revised manuscript received August 28, 2009, accepted August 30, 2009.

^_* Reprints requests and correspondence: Dr. Michael J. Ackerman, Director, Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, 200 First Street SW, Rochester, Minnesota 55905 (Email: ackerman.michael{at}mayo.edu).

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.

Key Words: ryanodine receptor • catecholaminergic polymorphic ventricular tachycardia • sudden cardiac death • exertional syncope

Abbreviations and Acronyms   CPVT = catecholaminergic polymorphic ventricular tachycardia   DNA = deoxyribonucleic acid   LQTS = long QT syndrome   QTc = corrected QT interval   RyR2 = cardiac ryanodine receptor

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