AUTHOR=Shin Ju Hyeon , Park Taek Kyu , Chang Sung-A. , Jang Shin Yi , Huh June , Seol Chang Ahn , Park Kyoung-Jin , Kim Sung Hoon , Kim Duk-Kyung , Gwag Hye Bin , Jang Mi-Ae 

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

JOURNAL=Frontiers in Genetics

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2025.1581535

DOI=10.3389/fgene.2025.1581535

ISSN=1664-8021

ABSTRACT=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 RYR2 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 RYR2 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 RYR2 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 RYR2 indel variant responsible for CPVT and expanded the mutational spectrum of RYR2-related CPVT, emphasizing the importance of comprehensive genetic approaches for variant classification.