Arrhythmias & electrophysiology
Calcium release channel deficiency syndrome in patients diagnosed with idiopathic ventricular fibrillation and decedents classified as sudden unexplained death in the young
Authors' conclusion
CRCDS 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.
Study context
- Population
- Patients with idiopathic VF and decedents classified as sudden unexplained death in the young, with RYR2 genetic analysis
- Participants
- 169 vs 279
- Exposure
- Idiopathic ventricular fibrillation (IVF) vs sudden unexplained death in the young (SUDY)
- IVFn = 169
- SUDYn = 279
- Outcome
- Prevalence of potential calcium release channel deficiency syndrome (CRCDS)-causative RYR2 variants (ultra-rare, <0.005% in gnomAD, nonsynonymous)
Main finding
As reported in the abstract
Ultra-rare RYR2 variant carriage
| Group | Value | Exertion-related SCA | Exertion-related SCD | Rest-related SCD |
|---|---|---|---|---|
| IVF | 3% | 6/67 (9%) | ||
| SUDY | 11% | 20/83 (24%) | 11/196 (6%) |
Value
IVF3%
SUDY11%
Exertion-related SCA
IVF6/67 (9%)
SUDY— not stated in the abstract
Exertion-related SCD
IVF— not stated in the abstract
SUDY20/83 (24%)
Rest-related SCD
IVF— not stated in the abstract
SUDY11/196 (6%)
Observational data: associations, not effects.
Further findings
Loss-of-function (LOF) RYR2 variant in SUDY
- LOF variant, of 14 with functionally characterized variants
- 5 (2% of total cohort)
- LOF variant, exertion-related SUDY
- 4/56 (7%)
Electrocardiogram (ECG) findings in IVF RYR2 carriers
- Distinct RYR2 variants (2 previously characterized as LOF)
- 6
- All exhibited normal resting and stress ECGs
Original publication
Calcium release channel deficiency syndrome in patients diagnosed with idiopathic ventricular fibrillation and decedents classified as sudden unexplained death in the young. Europace. Published 5 March 2026. doi:10.
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