{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T13:53:39Z","timestamp":1779371619496,"version":"3.53.1"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2021R1C1C1005725"],"award-info":[{"award-number":["2021R1C1C1005725"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>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 <jats:italic>RYR2<\/jats:italic> 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 <jats:italic>RYR2<\/jats:italic> 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 <jats:italic>RYR2<\/jats:italic> 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 <jats:italic>RYR2<\/jats:italic> indel variant responsible for CPVT and expanded the mutational spectrum of <jats:italic>RYR2<\/jats:italic>-related CPVT, emphasizing the importance of comprehensive genetic approaches for variant classification.<\/jats:p>","DOI":"10.3389\/fgene.2025.1581535","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:45:59Z","timestamp":1750225559000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel causative RYR2 indel variant with exon and intron involvement inducing exon 13 skipping in a family exhibiting catecholaminergic polymorphic ventricular tachycardia"],"prefix":"10.3389","volume":"16","author":[{"given":"Ju Hyeon","family":"Shin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taek Kyu","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-A.","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin Yi","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"June","family":"Huh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Ahn","family":"Seol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoung-Jin","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Hoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duk-Kyung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Bin","family":"Gwag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Ae","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.hrthm.2016.10.015","article-title":"A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia","volume":"14","author":"Fujii","year":"2017","journal-title":"Heart Rhythm"},{"key":"B3","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The genotype-tissue expression (GTEx) project","volume":"45","year":"2013","journal-title":"Nat. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"897494","DOI":"10.3389\/fphar.2022.897494","article-title":"Structural insight into ryanodine receptor channelopathies","volume":"13","author":"Hadiatullah","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1161\/CIRCULATIONAHA.108.829267","article-title":"Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia","volume":"119","author":"Hayashi","year":"2009","journal-title":"Circulation"},{"key":"B6","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"9293","DOI":"10.3390\/ijms22179293","article-title":"Pediatric catecholaminergic polymorphic ventricular tachycardia: a translational perspective for the clinician-scientist","volume":"22","author":"Kallas","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.ccep.2023.05.003","article-title":"Calcium release deficiency syndrome: a new inherited arrhythmia syndrome","volume":"15","author":"Kallas","year":"2023","journal-title":"Card. Electrophysiol. Clin."},{"key":"B9","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1016\/j.str.2011.03.016","article-title":"The deletion of exon 3 in the cardiac ryanodine receptor is rescued by beta strand switching","volume":"19","author":"Lobo","year":"2011","journal-title":"Structure"},{"key":"B10","doi-asserted-by":"publisher","first-page":"8080","DOI":"10.1038\/s41467-024-51791-y","article-title":"Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders","volume":"15","author":"Miotto","year":"2024","journal-title":"Nat. Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1016\/j.hrthm.2013.05.014","article-title":"HRS\/EHRA\/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013","volume":"10","author":"Priori","year":"2013","journal-title":"Heart Rhythm"},{"key":"B12","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of medical genetics and Genomics and the association for molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1001\/jamacardio.2021.4458","article-title":"Clinical and functional characterization of ryanodine receptor 2 variants implicated in calcium-release deficiency syndrome","volume":"7","author":"Roston","year":"2022","journal-title":"JAMA Cardiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2698","DOI":"10.1016\/j.jacc.2020.04.004","article-title":"A population-based registry of patients with inherited cardiac conditions and resuscitated cardiac arrest","volume":"75","author":"Rucinski","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"W431","DOI":"10.1093\/nar\/gkab314","article-title":"Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures","volume":"49","author":"Sehnal","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"euad156","DOI":"10.1093\/europace\/euad156","article-title":"RYR2-ryanodinopathies: from calcium overload to calcium deficiency","volume":"25","author":"Steinberg","year":"2023","journal-title":"Europace"},{"key":"B17","doi-asserted-by":"publisher","first-page":"eaba7287","DOI":"10.1126\/scitranslmed.aba7287","article-title":"Cardiac ryanodine receptor calcium release deficiency syndrome","volume":"13","author":"Sun","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.4065\/79.11.1380","article-title":"Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner\/coroner's cases","volume":"79","author":"Tester","year":"2004","journal-title":"Mayo Clin. Proc."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2953","DOI":"10.1093\/eurheartj\/ehz309","article-title":"Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest","volume":"40","author":"van der Werf","year":"2019","journal-title":"Eur. Heart J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1007\/s12471-019-1250-5","article-title":"Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance","volume":"27","author":"van Lint","year":"2019","journal-title":"Neth. Heart J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1002\/joa3.12717","article-title":"European heart rhythm association (EHRA)\/Heart rhythm society (HRS)\/Asia pacific heart rhythm society (APHRS)\/Latin American heart rhythm society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases","volume":"38","author":"Wilde","year":"2022","journal-title":"J. Arrhythm."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1581535\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:46:01Z","timestamp":1750225561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1581535\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":21,"alternative-id":["10.3389\/fgene.2025.1581535"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1581535","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"article-number":"1581535"}}