{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T10:47:53Z","timestamp":1771066073893,"version":"3.50.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Truncating variations in the titin gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) and have been implicated in various arrhythmic and heart failure phenotypes. Nonetheless, predicting the pathogenicity of a distinct subtype of TTNtv, canonical splice-site variations (TTNcsv), remains challenging. Furthermore, the precise transcriptional and phenotypic consequences associated with TTNcsv remain unclear. We evaluated the transcriptional profiles of TTN in vitro, focusing on TTNcsv found in patients with cardiac dysfunction, and compared them with their phenotypic manifestations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Genome-wide linkage analysis, whole-exome sequencing, and whole-genome sequencing were performed on a five-generation family with cardiac conduction disturbance (CCD). In addition, whole-genome sequencing was performed on 402 Japanese biobank patients with cardiomyopathy (CM) or unidentified cardiac dysfunction. Transcriptional profiles of TTNcsv were evaluated by RNA-Seq of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and endomyocardial biopsy specimens, and by minigene assays. A rare segregating TTNcsv (c.49049-2A&amp;gt;C) was identified in the five-generation family with CCD. RNA-Seq and minigene assays revealed complex aberrant TTN splicing transcripts: predominantly non-truncating transcripts caused by an 18 bp in-frame deletion (83\u201390%) and minor truncating transcripts (10\u201317%). Two additional TTNcsv were identified in biobank participants by whole-genome sequencing. A minigene assay of TTNcsv c.67348+1G&amp;gt;A, identified in a CCD patient with mild cardiac dysfunction, revealed predominantly non-truncating transcripts (95%), caused by retention of a 90 bp in-frame intron, along with 5% truncating TTN transcripts, caused by a 50 bp frameshift deletion, mirroring the TTNcsv observed in the familial CCD. In contrast, the DCM-associated TTNcsv c.67637-2A&amp;gt;G generated 87% truncating TTN transcripts, attributed to frameshift intron retention and cryptic splicing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The clinical data from this family suggest a close association between TTNcsv and CCD, which may involve an increase in non-truncating transcripts. Further studies are required to determine their precise relationship and the underlying mechanisms.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf135","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T11:53:43Z","timestamp":1754049223000},"page":"1712-1721","source":"Crossref","is-referenced-by-count":2,"title":["Phenotypic spectrum of cardiac conduction disturbance and cardiomyopathy linked to titin canonical splice-site variants"],"prefix":"10.1093","volume":"121","author":[{"given":"Taisuke","family":"Ishikawa","sequence":"first","affiliation":[{"name":"Omics Research Center, National Cerebral and Cardiovascular Center , Suita ,","place":["Japan"]},{"name":"Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University , Kagoshima ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Kimoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Seki","sequence":"additional","affiliation":[{"name":"Center for Medical and Nursing Education, Department of Preventive Medicine, Department of Cardiology, Tokyo Women\u2019s Medical University , Tokyo ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manabu","family":"Shirai","sequence":"additional","affiliation":[{"name":"Omics Research Center, National Cerebral and Cardiovascular Center , Suita ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Uto","sequence":"additional","affiliation":[{"name":"Department of Pathology, Nihon University School of Medicine , Tokyo ,","place":["Japan"]},{"name":"Department of Surgical Pathology, Tokyo Women\u2019s Medical University , Tokyo ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-5335","authenticated-orcid":false,"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University , Kyoto ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Kitai","sequence":"additional","affiliation":[{"name":"Department of Heart Failure, National Cerebral and Cardiovascular Center Hospital , Suita ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Mishima","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki 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,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0148-9787","authenticated-orcid":false,"given":"Pierre","family":"Lindenbaum","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Inserm UMR 1087 \/ CNRS UMR 6291, Nantes Universit\u00e9, CNRS, INSERM, l\u2019institut du thorax , IRS-UN, 8 Quai Moncousu, BP 70721, Nantes 44007 ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6651-1696","authenticated-orcid":false,"given":"Florence","family":"Kyndt","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax , Nantes ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adeline","family":"Goudal","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique M\u00e9dicale, CHU Nantes , Nantes ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihide","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Transplantation, National Cerebral and Cardiovascular Center , Suita ,","place":["Japan"]},{"name":"Faculty and Graduate School of Nursing, Senri Kinran University , Suita ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Fujita","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, National Cerebral and Cardiovascular Center , Suita ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7729-1836","authenticated-orcid":false,"given":"Kinta","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Cerebral and Cardiovascular Center , Suita 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,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7722-7348","authenticated-orcid":false,"given":"Christian","family":"Dina","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Inserm UMR 1087 \/ CNRS UMR 6291, Nantes Universit\u00e9, CNRS, INSERM, l\u2019institut du thorax , IRS-UN, 8 Quai Moncousu, BP 70721, Nantes 44007 ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xavier","family":"Estivill","sequence":"additional","affiliation":[{"name":"Genes and Disease Program, Centre for Genomic Regulation and Pompeu Fabra University , Barcelona 08002 ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Ossowski","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen , T\u00fcbingen 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