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Functional Characterization of Endogenously Expressed Human RYR1 Variants

Functional Characterization of Endogenously Expressed Human RYR1 Variants

Published on: June 9, 2021

Diverse Phenotypic Manifestations in a Family with a Novel RYR2 E4107A Variant

Hiroshi Hasegawa¹, Shuntaro Tamura¹, Tadashi Nakajima¹

¹Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine.

International Heart Journal

|June 2, 2024

Abstract:

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Conversely, RyR2 loss-of-function mutations cause a new disease entity, termed calcium release deficiency syndrome (CRDS), which may include RYR2-related long QT syndrome (LQTS). Importantly, unlike CPVT, patients with CRDS do not always exhibit exercise- or epinephrine-induced ventricular arrhythmias, which precludes a diagnosis of CRDS. Here we report a boy and his father, who both experienced exercise-induced cardiac events and harbor the same RYR2 E4107A variant. In the boy, an exercise stress test (EST) and epinephrine provocation test (EPT) did not induce any ventricular arrhythmias. QTc was slightly prolonged (QTc: 474 ms), and an EPT induced QTc prolongation (QTc-baseline: 466 ms, peak: 532 ms, steady-state: 527 ms). In contrast, in his father, QTc was not prolonged (QTc: 417 ms), and neither an EST nor EPT induced QTc prolongation. However, an EST induced multifocal premature ventricular contraction (PVC) bigeminy and bidirectional PVC couplets. Thus, they exhibited distinct clinical phenotypes: the boy exhibited LQTS (or CRDS) phenotype, whereas his father exhibited CPVT phenotype. These findings suggest that, in addition to the altered RyR2 function, other unidentified factors, such as other genetic, epigenetic, and environmental factors, and aging, may be involved in the diverse phenotypic manifestations. Considering that a single RYR2 variant can cause both CPVT and LQTS (or CRDS) phenotypes, in cascade screening of patients with CPVT and CRDS, an EST and EPT are not sufficient and genetic analysis is required to identify individuals who are at increased risk for life-threatening arrhythmias.

Insights

A single RYR2 gene variant can cause distinct cardiac conditions, including catecholaminergic polymorphic ventricular tachycardia (CPVT) and calcium release deficiency syndrome (CRDS). Genetic testing is crucial for identifying at-risk individuals, as standard tests may not reveal all potential arrhythmias.

Area of Science:

Cardiovascular Genetics
Molecular Cardiology
Cardiac Electrophysiology

Background:

Gain-of-function RYR2 mutations cause CPVT, while loss-of-function mutations define CRDS, potentially including RYR2-related LQTS.
CRDS diagnosis is challenging as patients may not exhibit exercise- or epinephrine-induced arrhythmias, unlike CPVT.
A family with the RYR2 E4107A variant presented with diverse clinical phenotypes, highlighting diagnostic complexities.

Purpose of the Study:

To investigate the phenotypic variability associated with the RYR2 E4107A variant in a father-son cohort.
To determine the diagnostic utility of exercise stress tests (EST) and epinephrine provocation tests (EPT) in RYR2-related cardiac disorders.
To emphasize the necessity of genetic analysis in cascade screening for CPVT and CRDS.

Main Methods:

Clinical evaluation of a father and son with the RYR2 E4107A variant.
Performance of exercise stress tests (EST) and epinephrine provocation tests (EPT).
Electrocardiographic (ECG) monitoring, including QTc interval measurements and arrhythmia detection.

Main Results:

The son exhibited an LQTS (or CRDS) phenotype with QTc prolongation during EPT, despite no arrhythmias on EST or EPT.
The father presented with a CPVT phenotype, experiencing multifocal premature ventricular contractions (PVCs) and bidirectional PVCs during EST, with normal QTc.
Distinct clinical presentations underscore the influence of factors beyond the RYR2 variant itself.

Conclusions:

A single RYR2 variant can manifest as either CPVT or LQTS/CRDS, indicating complex genotype-phenotype correlations.
EST and EPT are insufficient for diagnosing all RYR2-related arrhythmias, necessitating genetic screening.
Unidentified genetic, epigenetic, environmental factors, and aging may contribute to the diverse clinical outcomes in RYR2-associated channelopathies.

Read full analysis

Keywords:

Calcium release deficiency syndrome Cardiac ryanodine receptor Catecholaminergic polymorphic ventricular tachycardia Long QT syndrome

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