Patient Information
This case series involves a 5-generation French Canadian family presenting with a significant history of unexplained sudden cardiac arrest and sudden cardiac death. Among the family members evaluated at a multidisciplinary cardiac genetics clinic in a tertiary referral center in Canada, five individuals identified as carriers of a novel RYR2 gene variant were studied. The affected individuals included two females and three males, with an age range of 17 to 59 years at their first clinical evaluation. The family history was notable for multiple instances of sudden unexplained deaths and sudden cardiac arrests occurring at relatively young ages, prompting referral for genetic and clinical evaluation.
Diagnosis
The clinical evaluation involved using a recently proposed burst pacing provocation test designed to detect calcium release deficiency syndrome (CRDS), a newly characterized inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac ryanodine receptor gene (RYR2). The diagnosis was supported by the detection of diagnostic T-wave augmentation after burst pacing and/or spontaneous atrial or ventricular arrhythmias detected during ambulatory monitoring.
Functional studies confirmed the pathogenicity of a novel RYR2 variant, p.Glu336Gly, which was demonstrated to cause a loss-of-function effect on calcium release channels. This variant represents the first reported loss-of-function mutation in a mutational hot spot previously associated exclusively with gain-of-function mutations causing arrhythmia syndromes like catecholaminergic polymorphic ventricular tachycardia (CPVT).
Importantly, the diagnostic sensitivity of the provocation test depended on identification of pause-dependent T-wave augmentation, underscoring the test’s utility in the clinical setting.
Differential Diagnosis
The differential diagnosis for sudden cardiac death in families with inherited arrhythmia syndromes typically includes:
– Catecholaminergic polymorphic ventricular tachycardia (CPVT): Usually caused by gain-of-function RYR2 mutations; differs in pathophysiology from CRDS.
– Long QT Syndrome (LQTS): Typically characterized by prolonged QT interval on ECG and Torsades de Pointes.
– Brugada Syndrome: Characteristic ECG patterns and sodium channel mutations.
– Arrhythmogenic right ventricular cardiomyopathy (ARVC): Structural heart abnormalities with fibrofatty infiltration.
– Idiopathic ventricular fibrillation: When no structural or genetic cause is identified.
These conditions were considered but were ruled out based on genetic testing results, absence of typical ECG features, and the presence of a loss-of-function RYR2 variant confirmed functionally.
Treatment and Management
Management focused on risk stratification and prevention of sudden cardiac death in variant carriers. Given the novelty of CRDS and its clinical diagnostic method, treatment strategies were extrapolated from management principles in inherited arrhythmia syndromes and guided by the individual clinical presentations. Interventions included:
– Close cardiac monitoring using ambulatory ECG devices to detect arrhythmias.
– Use of antiarrhythmic medications as indicated, though specific drug efficacy for CRDS is not yet well-defined.
– Consideration of implantable cardioverter-defibrillator (ICD) placement in high-risk individuals given the family history of sudden death.
– Counseling regarding avoidance of triggers that may precipitate arrhythmias.
– Regular follow-up at the specialized cardiac genetics clinic for ongoing evaluation and adjustment of management plans.
Outcome and Prognosis
The five RYR2 variant carriers demonstrated clinically diagnostic responses to the burst pacing provocation test, confirming CRDS diagnosis, which allowed targeted counseling and risk assessment. Long-term prognosis remains uncertain given the recent recognition of CRDS as a unique entity, but early identification is expected to improve management and outcomes. The identification of loss-of-function RYR2 variants expands the clinical and genetic spectrum of inherited arrhythmia syndromes, facilitating enhanced monitoring and prophylactic treatment strategies to prevent sudden cardiac death.
Discussion
Calcium release deficiency syndrome represents an emergent paradigm in inherited arrhythmia disorders, distinct from better-characterized conditions such as CPVT. This case series is the first to apply a novel clinical diagnostic tool—the burst pacing provocation test—to establish CRDS diagnosis in a family with unexplained sudden cardiac death. The reliance on identifying pause-dependent T-wave augmentation post-burst pacing was critical to enhancing diagnostic sensitivity.
The functional characterization of a previously undescribed RYR2-p.Glu336Gly variant as loss-of-function challenges prior assumptions that pathogenic RYR2 mutations predominantly induce gain-of-function effects. This finding broadens the mutational landscape and informs future genetic screening and precision medicine approaches.
The study underscores the importance of incorporating tailored provocation tests in clinical practice to detect subtle electrophysiological abnormalities. Furthermore, the findings highlight the urgent need for developing evidence-based risk stratification and management guidelines specific to CRDS.
Overall, this case series advances understanding of CRDS pathophysiology, diagnosis, and clinical implications, emphasizing multidisciplinary collaboration in genetic cardiology and electrophysiology for optimized patient care.
References
1. Isbister JC, Tian S, Wang R, et al. Clinical Diagnosis of Calcium Release Deficiency Syndrome in a Family With Sudden Cardiac Death. JAMA Cardiol. 2026;11(7):674-678. doi:10.1001/jamacardio.2026.0154
2. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10(12):1932-1963.
3. Watanabe H, Chopra N, Laver D, et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15(4):380-383.
4. Roston TM, Pavlovic D, Wilde AAM, Bhuiyan ZA. Ryanodine receptor type 2 (RYR2) genetic abnormalities in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Europace. 2019;21(4):552-558.
5. Tester DJ, Pollevick GD, Kapplinger JD, et al. A novel variant in RYR2 gene causing catecholaminergic polymorphic ventricular tachycardia with variable penetrance. Heart Rhythm. 2012;9(6):1013-1020.
The detailed exploration of this family and the novel diagnostic test represents a significant step forward in clinical cardiology, genetic diagnostics, and personalized care for inherited arrhythmia syndromes.