ArticleEuropace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology2026
Calcium release channel deficiency syndrome in patients diagnosed with idiopathic ventricular fibrillation and decedents classified as sudden unexplained death in the young.
Lucilla Giammarino, Raquel Neves, David J Tester, Sahej Bains, Vanessa Karlinski Vizentin, J Martijn Bos, John R Giudicessi, Michael J Ackerman
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Lucilla GiammarinoDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.ORCID 0000-0002-2100-0160 Raquel NevesDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.ORCID 0000-0003-2619-0036 David J TesterDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.
Sahej BainsDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.ORCID 0000-0002-1357-7656 Vanessa Karlinski VizentinDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.
J Martijn BosDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.ORCID 0000-0002-3635-2003 John R GiudicessiDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.
Michael J AckermanDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.ORCID 0000-0002-8011-3333 Funding
Calcium Release Channel Deficiency SyndromeR01HL171023 · NHLBI · MAYO CLINIC ROCHESTER · PI MICHAEL JOHN ACKERMAN · 2024 to 2026
$1.2MMayo Clinic Center for Translational Science Activities UL1TR002377Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death ProgramNational Heart, Lung, and Blood Institute of the National Institutes of Health R01HL171023NCATS NIH HHSNHLBI NIH HHS R01 HL171023NIH HHSPostdoc Mobility Fellowship from the Swiss National Science Foundation
6 · The paper itselfAbstract
aimsCalcium release channel deficiency syndrome (CRCDS) results from loss-of-function (LOF) variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) without abnormalities on a stress electrocardiogram (ECG). Undetected CRCDS may underlie idiopathic ventricular fibrillation (IVF) and sudden unexplained death in the young (SUDY). We aimed to determine the prevalence of potential CRCDS-causative RYR2 variants in IVF and SUDY. METHODS AND
resultsWe reviewed clinical evaluation and RYR2 genetic analysis of 169 IVF patients and 279 SUDY victims. Only ultra-rare (<0.005% in gnomAD) nonsynonymous RYR2 variants were considered potentially pathogenic. Among IVF patients, 6/169 (3%) overall-and 6/67 (9%) with exertion-related SCA-harboured an RYR2 variant and represent potential CRCDS cases. All exhibited normal resting and stress ECGs. Genetic analysis revealed six distinct RYR2 variants, two previously characterized as LOF. In SUDY, 31/279 victims (11%) had a RYR2 variant (30 unique variants), predominantly observed in exertion-related SCD 20/83 (24%) vs. rest-related 11/196 (6%). Of the 14 SUDY victims with functionally characterized RYR2 variants, five (2% of total cohort) had a LOF variant; among the 56 exertion-related SUDY cases, four (7%) had a LOF variant.
conclusionCRCDS may account for 3% of IVF overall and 9% of exertion-related SCA in IVF. Ultra-rare RYR2 variants may underlie up to 11% of SUDY, with 65% of RYR2-positive cases occurring during exertion. LOF-RYR2 variants may contribute to ≥7% of exercise-associated SUDY. Accurate identification of the underlying ryanodinopathy is essential for clinical management of affected patients.
Indexed as
Death, Sudden, CardiacRyanodine Receptor Calcium Release ChannelVentricular FibrillationAdolescentAdultElectrocardiographyFemaleGenetic Predisposition to DiseaseGenetic TestingHumansMalePhenotypePrevalenceRisk FactorsYoung AdultRyanodine Receptor Calcium Release ChannelRyR2 protein, humanArrhythmiasCalcium release channel deficiency syndromeGeneticsRYR2Sudden cardiac arrestSyncope
Identifiers
PMID41785165
PMCPMC12962230
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