Evaluation of A Clinical Diagnostic Test for CRDS

Summary

Calcium Release Deficiency Syndrome (CRDS) is a novel inherited arrhythmia syndrome secondary to RyR2 loss-of-function that confers a risk of sudden cardiac death. Diagnosis of CRDS presently requires cellular-based in vitro confirmation that an RyR2 variant causes loss-of-function. We hypothesize that CRDS can be diagnosed clinically through evaluation of the repolarization response to brief tachycardia, mediated by cardiac pacing, and a subsequent pause.

Eligibility

Cohort 1: Calcium Release Deficiency Syndrome (CRDS) Cases

Inclusion criteria:

• Presence of an RyR2 variant confirmed to be loss-of-function on in vitro testing

Exclusion criteria:

• Unable to provide informed consent

Cohort 2: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cases

Inclusion criteria:

* Satisfy a clinical phenotype consistent with the Expert Consensus Statement
* Presence of a confirmed or presumed pathogenic gain-of-function RyR2 variant OR homozygous or compound heterozygous for likely pathogenic/pathogenic CASQ2 variants

Exclusion criteria:

* Unable to provide informed consent
* Use of a QT prolonging medication, aside from flecainide, at the time of the burst pacing maneuvers

Cohort 3: Survivors of Unexplained Cardiac Arrest (UCA)

Inclusion criteria:

* Cardiac arrest requiring cardioversion or defibrillation that remains unexplained following an ECG, echocardiogram, coronary assessment, cardiac MRI, and exercise treadmill test
* Undergone genetic testing that includes screening of RyR2\*

Exclusion criteria:

* Unable to provide informed consent
* Use of a QT prolonging medication at the time of the burst pacing maneuvers

  * Among survivors of UCA that possess a rare RyR2 variant in the absence of a CPVT phenotype, in vitro functional testing will be performed in order to confirm it is not loss- or gain-of-function (and will be arranged through the laboratory of Dr. Wayne Chen at the University of Calgary).

Cohort 4: SVT controls

Inclusion criteria:

• Undergoing an invasive electrophysiology study

Exclusion criteria:

* Ventricular cardiomyopathy
* Ventricular pre-excitation
* Long QT syndrome
* Use of a QT prolonging medication at the time of the EP study
* Use of a Class I or Class III anti-arrhythmic drug at the time of the EP study
* Known obstructive coronary artery disease (existing coronary stenosis \>50%)
* Unable to provide informed consent

Conditions2

Locations3 sites

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