{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:18:40Z","timestamp":1783523920155,"version":"3.55.0"},"reference-count":10,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:sec id=\"ab-hbr260011-1\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>\n                      Calcium release deficiency syndrome (CRDS) is a recently described inherited arrhythmia caused by loss-of-function variants in the cardiac ryanodine receptor (\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      ). Diagnosis currently requires in vitro functional testing and availability limits diagnosis; a recently proposed burst pacing provocation test offers a potential clinical diagnostic tool, but its performance remains to be validated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hbr260011-2\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To demonstrate how the novel CRDS provocation test can clinically establish the diagnosis in a family with unexplained sudden cardiac arrest and death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hbr260011-3\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>This case series examines a 5-generation pedigree with clinical, genetic, and functional data conducted among a large French Canadian family with an extensive history of unexplained sudden cardiac arrest and death. The study was conducted at a multidisciplinary cardiac genetics clinic at a tertiary referral center in Canada. Data were gathered and analyzed from June 2024 through March 2025.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hbr260011-4\">\n                    <jats:title>Exposures<\/jats:title>\n                    <jats:p>Clinical provocation with burst pacing and\/or spontaneous atrial or ventricular arrhythmia detected on ambulatory monitoring.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hbr260011-5\">\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>The primary outcome was diagnostic T-wave augmentation following burst pacing or spontaneous atrial or ventricular arrhythmia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hbr260011-6\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this case series, 5\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      variant carriers (2 female [40%]; age range at first evaluation, 17-59 years) demonstrated diagnostic T-wave augmentation after pacing or spontaneous arrhythmia consistent with CRDS. Pause dependence was essential for diagnostic sensitivity. Functional studies of the novel RYR2-p.Glu336Gly variant confirmed that it results in loss of function. This appears to be the first such variant reported within a hot spot previously restricted to gain-of-function variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-hbr260011-7\">\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>This case series provides the first clinical application of the CRDS provocation test in a family with a history of unexplained sudden cardiac death. Findings underscore the diagnostic importance of pause dependence and highlight the need for improved risk stratification in CRDS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamacardio.2026.1067","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T15:30:25Z","timestamp":1779895825000},"page":"674","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Diagnosis of Calcium Release Deficiency Syndrome in a Family With Sudden Cardiac Death"],"prefix":"10.1001","volume":"11","author":[{"given":"Julia C.","family":"Isbister","sequence":"first","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada"},{"name":"Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Tian","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiwu","family":"Wang","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Paul","family":"Estillore","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannie","family":"Gagnon","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Robb","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Neveu","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Rivard","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada"},{"name":"Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Cadrin-Tourigny","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada"},{"name":"Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. R. Wayne","family":"Chen","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafik","family":"Tadros","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Montreal, Quebec, Canada"},{"name":"Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"579","key":"hbr260011r1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1126\/scitranslmed.aba7287","article-title":"Cardiac ryanodine receptor calcium release deficiency syndrome.","volume":"13","author":"Sun","year":"2021","journal-title":"Sci Transl Med"},{"issue":"3","key":"hbr260011r2","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1001\/jama.2024.8599","article-title":"A clinical diagnostic test for calcium release deficiency syndrome.","volume":"332","author":"Ni","year":"2024","journal-title":"JAMA"},{"issue":"4","key":"hbr260011r3","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1161\/CIRCULATIONAHA.109.853143","article-title":"Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER).","volume":"120","author":"Krahn","year":"2009","journal-title":"Circulation"},{"issue":"5","key":"hbr260011r4","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"1","key":"hbr260011r5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.121.003589","article-title":"Provocation testing and therapeutic response in a newly described channelopathy: RyR2 calcium release deficiency syndrome.","volume":"15","author":"Ormerod","year":"2022","journal-title":"Circ Genom Precis Med"},{"issue":"1","key":"hbr260011r6","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1001\/jamacardio.2021.4458","article-title":"Clinical and functional characterization of ryanodine receptor 2 variants implicated in calcium-release deficiency syndrome.","volume":"7","author":"Roston","year":"2022","journal-title":"JAMA Cardiol"},{"issue":"9","key":"hbr260011r7","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.121.010013","article-title":"Human RyR2 (ryanodine receptor 2) loss-of-function mutations: clinical phenotypes and in vitro characterization.","volume":"14","author":"Li","year":"2021","journal-title":"Circ Arrhythm Electrophysiol"},{"issue":"7","key":"hbr260011r8","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1161\/CIRCRESAHA.110.226845","article-title":"Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis.","volume":"108","author":"Priori","year":"2011","journal-title":"Circ Res"},{"issue":"12","key":"hbr260011r9","doi-asserted-by":"publisher","first-page":"7736","DOI":"10.1074\/jbc.M114.618827","article-title":"Roles of the NH2-terminal domains of cardiac ryanodine receptor in Ca2+ release activation and termination.","volume":"290","author":"Liu","year":"2015","journal-title":"J Biol Chem"},{"issue":"3","key":"hbr260011r10","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.ccep.2023.05.003","article-title":"Calcium release deficiency syndrome: a new inherited arrhythmia syndrome.","volume":"15","author":"Kallas","year":"2023","journal-title":"Card Electrophysiol Clin"}],"container-title":["JAMA Cardiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamacardiology\/articlepdf\/2849618\/jamacardiology_isbister_2026_br_260011_1782314641.88238.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:00:19Z","timestamp":1783522819000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamacardiology\/fullarticle\/2849618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":10,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamacardio.2026.1067","relation":{},"ISSN":["2380-6583"],"issn-type":[{"value":"2380-6583","type":"print"}],"subject":[],"published":{"date-parts":[[2026,7,1]]}}}