Evaluation of A Clinical Diagnostic Test for CRDS

RyR2 loss-of-function variants have recently been established as causative for a new disease termed calcium release deficiency syndrome (CRDS) that confers a risk of malignant ventricular arrhythmias and sudden cardiac death. RyR2 encodes the cardiac ryanodine receptor, the calcium release channel on the sarcoplasmic reticulum that mediates excitation-contraction coupling through calcium-induced calcium-release. In contrast to CRDS, pathogenic RyR2 gain-of-function variants result in an autosomal dominant form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The adrenergic-mediated ventricular arrhythmias characteristic of CPVT can be readily reproduced on exercise stress testing (EST), making EST the standard clinical diagnostic tool for CPVT.

In contrast to CPVT, the CRDS clinical phenotype is concealed with standard cardiac testing tools and its diagnosis presently requires cellular-based in vitro confirmation that an RyR2 variant causes loss-of-function. Beyond the significant time delay associated with in vitro functional analysis, this testing requires specialized expertise that is not widely available and remains research-based, making it impractical for routine use in clinical care. In this overall context, it is likely that the vast majority of global CRDS cases have yet to be diagnosed.

A prior report of an "atypical CPVT" family carrying an RyR2-p.M4109R variant observed marked and transient repolarization changes following pacing mediated tachycardia and a subsequent pause. Since publication of this report, in vitro characterization of the RyR2-p.M4109R variant has confirmed its being loss-of-function and the familial diagnosis has been revised to CRDS. Driven by these observations and promising preliminary findings, the DIAGNOSE CRDS study seeks to further investigate this apparent electrocardiographic signature of CRDS following brief tachycardia and subsequent pause as a potential method to clinically diagnose the condition.

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