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

Ju Hyeon Shin¹Taek Kyu Park¹Sung-A Chang¹Shin Yi Jang¹June Huh¹Chang Ahn Seol²Kyoung-Jin Park³Sung Hoon Kim³Duk-Kyung Kim³Hye Bin Gwag^3*Mi-Ae Jang^1*

• ¹Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea
• ²Green Cross Genome, Yongin-si, Republic of Korea
• ³Samsung Changwon Hospital, School of Medicine, Sungkyunkwan University, Changwon, South Gyeongsang, Republic of Korea

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder marked by exercise or stress-induced arrhythmias, leading to syncope or sudden cardiac death. RYR2 gene mutations can cause either CPVT or calcium release deficiency syndrome, with varying impacts on calcium release in cardiomyocytes. They are predominantly missense variants associated with a gain-of-function mechanism. In this study, we report a novel pathogenic RYR2 indel variant in a family afflicted with CPVT through comprehensive molecular investigation. The proband, a 15-year-old female, 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 interaction. This discovery led to classification of the variant as a likely pathogenic variant. This study identified a novel RYR2 indel variant responsible for CPVT and expanded the mutational spectrum of RYR2-related CPVT, emphasizing the importance of comprehensive genetic approach for variant classification.