JAMA cardiology · 2026
Clinical Diagnosis of Calcium Release Deficiency Syndrome in a Family With Sudden Cardiac Death.
СтатьяНазвание и аннотация: Перевод в очереди
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Isbister Julia C, Tian Shanshan, Wang Ruiwu, Estillore John Paul, Gagnon Johannie, Robb Laura, Neveu Benjamin, Rivard Lena, Cadrin-Tourigny Julia, Roberts Jason D, Chen S R Wayne, Tadros Rafik
Аннотация
IMPORTANCE: Calcium release deficiency syndrome (CRDS) is a recently described inherited arrhythmia caused by loss-of-function variants in the cardiac ryanodine receptor (RYR2). 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.
OBJECTIVE: To demonstrate how the novel CRDS provocation test can clinically establish the diagnosis in a family with unexplained sudden cardiac arrest and death.
DESIGN, SETTING, AND PARTICIPANTS: 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.
EXPOSURES: Clinical provocation with burst pacing and/or spontaneous atrial or ventricular arrhythmia detected on ambulatory monitoring.
MAIN OUTCOMES AND MEASURES: The primary outcome was diagnostic T-wave augmentation following burst pacing or spontaneous atrial or ventricular arrhythmia.
RESULTS: In this case series, 5 RYR2 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.
CONCLUSIONS AND RELEVANCE: 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.
OBJECTIVE: To demonstrate how the novel CRDS provocation test can clinically establish the diagnosis in a family with unexplained sudden cardiac arrest and death.
DESIGN, SETTING, AND PARTICIPANTS: 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.
EXPOSURES: Clinical provocation with burst pacing and/or spontaneous atrial or ventricular arrhythmia detected on ambulatory monitoring.
MAIN OUTCOMES AND MEASURES: The primary outcome was diagnostic T-wave augmentation following burst pacing or spontaneous atrial or ventricular arrhythmia.
RESULTS: In this case series, 5 RYR2 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.
CONCLUSIONS AND RELEVANCE: 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.