Novel causative RYR2 indel variant with exon and intron involvement inducing exon 13 skipping in a family exhibiting catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder marked by exercise or stress-induced arrhythmias that lead to syncope or sudden cardiac death. Mutations of the <i>RYR2</i> gene can cause either CPVT or calcium release deficiency syndrome, with varying impacts on calcium release in cardiomyocytes. These mutations are predominantly missense variants associated with a gain-of-function mechanism. In this report, we present a novel pathogenic <i>RYR2</i> indel variant in a family afflicted with CPVT based on comprehensive molecular investigations. The proband was a 15-year-old girl who suffered a cardiac arrest during exercise and exhibited frequent premature ventricular beats on a treadmill test, which was consistent with CPVT. Using next-generation sequencing and Sanger sequencing, a novel <i>RYR2</i> indel variant, NM_001035.3:c.1006-44_1007delinsATTTTG, was identified. Sanger sequencing confirmed the presence of this variant in her mother, who also showed frequent premature ventricular beats on a treadmill test. Further RNA analysis revealed that this variant caused aberrant splicing, resulting in the skipping of exon 13 (r.1006_1170del), which would disrupt the intramolecular domain interactions. This discovery led to the classification of the variant as a likely pathogenic variant. We identified a novel <i>RYR2</i> indel variant responsible for CPVT and expanded the mutational spectrum of <i>RYR2</i>-related CPVT, emphasizing the importance of comprehensive genetic approaches for variant classification.