# Calcium release channel deficiency syndrome in patients diagnosed with idiopathic ventricular fibrillation and decedents classified as sudden unexplained death in the young

## TL;DR

This study finds that a genetic condition affecting calcium channels may cause sudden cardiac events in people with no obvious heart problems.

## Contribution

The study identifies the prevalence of RYR2 gene variants in IVF and SUDY cases, linking them to a newly recognized syndrome.

## Key findings

- CRCDS may account for 3% of IVF and 9% of exertion-related sudden cardiac arrest in IVF patients.
- RYR2 variants were found in 11% of SUDY cases, with 65% of these occurring during exertion.
- Loss-of-function RYR2 variants contribute to at least 7% of exercise-related SUDY cases.

## Abstract

Calcium 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.

We 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.

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. Accurate identification of the underlying ryanodinopathy is essential for clinical management of affected patients.

Graphical AbstractPrevalence and clinical presentation of calcium release channel deficiency syndrome (CRCDS) in idiopathic ventricular fibrillation (IVF) and sudden unexplained death in the young (SUDY). Loss-of-function (LOF) pathogenic variants in the RYR2 gene alter physiological sarcoplasmic reticulum (SR) calcium (Ca²⁺) release, causing CRCDS. Despite preserved cardiac structure/function and negative stress ECGs, CRCDS predisposes individuals to exertion-related sudden cardiac arrest (SCA) or sudden cardiac death (SCD). In this study, 169 IVF patients underwent RYR2 genetic testing, revealing a 3% prevalence of potential CRCDS cases, of whom all were associated with exertion-related SCA. Molecular autopsy of 279 SUDY victims identified 30 RYR2 pathogenic variants in 31 cases overall (11%), with at least 2% of cases possessing CRCDS-causing variants and predominantly associated with exertion-related SCD. Abbreviations: Ca²⁺, calcium ions; CRCDS, calcium release channel deficiency syndrome; ECG, electrocardiogram; IVF, idiopathic ventricular fibrillation; LOF, loss-of-function; RYR2, ryanodine receptor 2 (gene); RyR2, ryanodine receptor 2 (protein), SCA, sudden cardiac arrest; SCD, sudden cardiac death; SR, sarcoplasmic reticulum; SUDY, sudden unexplained death in the young; TMD, transmembrane domain.For image description, please refer to the figure legend and surrounding text.

Prevalence and clinical presentation of calcium release channel deficiency syndrome (CRCDS) in idiopathic ventricular fibrillation (IVF) and sudden unexplained death in the young (SUDY). Loss-of-function (LOF) pathogenic variants in the RYR2 gene alter physiological sarcoplasmic reticulum (SR) calcium (Ca²⁺) release, causing CRCDS. Despite preserved cardiac structure/function and negative stress ECGs, CRCDS predisposes individuals to exertion-related sudden cardiac arrest (SCA) or sudden cardiac death (SCD). In this study, 169 IVF patients underwent RYR2 genetic testing, revealing a 3% prevalence of potential CRCDS cases, of whom all were associated with exertion-related SCA. Molecular autopsy of 279 SUDY victims identified 30 RYR2 pathogenic variants in 31 cases overall (11%), with at least 2% of cases possessing CRCDS-causing variants and predominantly associated with exertion-related SCD. Abbreviations: Ca²⁺, calcium ions; CRCDS, calcium release channel deficiency syndrome; ECG, electrocardiogram; IVF, idiopathic ventricular fibrillation; LOF, loss-of-function; RYR2, ryanodine receptor 2 (gene); RyR2, ryanodine receptor 2 (protein), SCA, sudden cardiac arrest; SCD, sudden cardiac death; SR, sarcoplasmic reticulum; SUDY, sudden unexplained death in the young; TMD, transmembrane domain.