PO30 Phenotypic variability of RyR2-related disease: A sudden cardiac death survivor with a rare splice-site variant

Abstract Background Calcium release deficiency syndrome (CRDS) is novel “ryanodinopathy” caused by loss-of-function mutations in the ryanodine receptor 2 (RyR2) gene, located on chromosome 1 (1q42.1–q43). It encodes the homotetrameric RyR2 channel which plays a vital role in cardiac excitation–contraction coupling. Multiple missense mutations in RyR2, including I3995V, D4646A and R4594K/I2075T have been associated with CRDS which often presents as sudden cardiac death (SCD). Diagnosis in relatives is challenging due to nonspecific findings such as non-sustained ventricular tachycardia (NSVT), a lack of abnormalities on exercise testing, and an absence of structural disease on cardiac imaging. Recently, a long-burst, long-pause, short-coupled (LBLPS) electrophysiology study (EPS) protocol has been developed, which reproducibly induced ventricular arrhythmias in carriers of the Ala4142Thr missense mutation. However, the role of these investigations in patients harbouring non-missense RyR2 variants, particularly splice variants or variants of uncertain significance (VUS), remains poorly defined. Purpose We aimed to characterize the clinical, electrophysiological, and genetic features of a woman who survived SCD and subsequently found to carry a rare RyR2 splice mutation, absent from major disease databases and not previously associated with “ryanodinopathies”. Methods A 41-year-old woman presented in 2013 following an out-of-hospital ventricular fibrillation arrest requiring multiple external defibrillations. Genetic testing targeted panels for arrhythmogenic cardiomyopathy (ACM), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome revealed a heterozygous VUS, c.1961+3AT, in the RyR2 gene. After recovery, she underwent implantation of a dual-chamber implantable cardioverter-defibrillator (ICD) and several investigations as detailed below. An LBLPS EPS protocol was performed at baseline and during flecainide infusion. Results Initial ECGs revealed transient QTc prolongation that later normalized, leaving a stable RSR pattern in V2 with T-wave inversion in V1–V2. Cardiac MRI showed mild right ventricular dilatation but no criteria for ACM. Coronary angiography, echocardiography, signal-averaged ECG, exercise testing, and ajmaline provocation were unrevealing. The LBLPS protocol did not induce ventricular arrhythmias. In 12 years of surveillance, only occasional NSVT but no sustained arrhythmia or ICD therapies were seen. Screening of her son and sibling identified no abnormalities. Conclusions We describe a unique case of a sudden cardiac death survivor with a splice-site RyR2 mutation who did not demonstrate typical CRDS features, including absence of inducibility with LBLPS EPS. This case highlights the phenotypic variability of RyR2-related disease and underscores the need for ongoing study of splice variants and other non-missense changes to clarify their pathogenic role.