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

Figures

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  Figure 1. Flow charts of patient selection and ultra-rare nonsynonymous RYR2 variants in the two cohorts. (A) IVF cohort: Among 169 IVF patients, six were identified as potential CRCDS cases, based on stress-test ECG and genetic findings. All experienced exertion-related SCA and carried six unique RYR2 variants, two of which were previously characterized as LOF. (B) SUDY cohort: Among 279 SUDY victims, 31 carried a RYR2 variant, corresponding to 30 unique variants. Of these, 20 variants were associated with exertion-related SCD. Functional data were available for 10 variants: 6 were GOF (CPVT1-associated) and 4 were LOF (CRCDS-associated).

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  Figure 2. Schematic representation of the RYR2 gene and RyR2 protein depicting all CRCDS-associated variants identified in our SUDY and IVF cohorts. (A) Linear RYR2 map indicating domains and variant clusters. (B) Tetrameric RyR2 structure representing the phosphorylated human RyR2 (closed state; PDB ID: 7U9Q28). (C) Single RyR2 subunit topology showing the localization of all CRCDS-associated RYR2 variants identified in this study in both cohorts.

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  Figure 3. Surface stress-test ECG traces obtained at peak exercise in the six potential CRCDS within our IVF cohort. Representative 12-lead surface stress ECGs are shown for each patient, similar recordings taken from lead V5 at the peak of exercise. Peak HR reached per patient is specified.

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  Figure 4. VF onset in a CRCDS patient as compared to a CPVT1 patient. Representative ICD tracings showing in two patients carrying a RYR2-pathogenic variant functionally characterized as either LOF in (A), or as GOF in (B). Arrows indicate detection and initiation of high-voltage defibrillation therapy (expressed in joules). (A) CRCDS patient (case 6, IVF cohort) showing sudden VF onset without preceding PVCs or arrhythmic progression detected prior major cardiac event. (B) CPVT1 patient (not part of the IVF cohort) demonstrating progressive, increasing ectopic activity and arrhythmic complexity preceding VF and subsequential ICD shock.

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  Figure 5. Autonomic contribution in SUDY and RYR2-positive SUDY cases. (A) Distribution of SCD autonomic triggers (exertion vs. rest) among all SUDY victims. (B) Distribution of autonomic triggers (exertion vs. rest) in RYR2-positive SUDY victims. Fisher’s exact test. (C) Proportion of CRCDS and CPVT1 cases among exertion-related RYR2-positive SUDY victims.