{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T16:58:26Z","timestamp":1785257906536,"version":"3.55.0"},"reference-count":24,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015550","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RC-2026-2801309"],"award-info":[{"award-number":["RC-2026-2801309"]}],"id":[{"id":"10.13039\/501100015550","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Founder mutations in MYBPC3 may contribute substantially to the genetic burden of hypertrophic cardiomyopathy (HCM) and provide important insights into genotype\u2013phenotype correlations and population-specific disease mechanisms. In this study, we investigated two recurrent canonical splice-site variants, MYBPC3 c.1458-1G&gt;A and c.3331-1G&gt;A, identified in patients with HCM from the Emilia-Romagna region of Northern Italy. Methods: Ninety-one unrelated patients with HCM carrying either MYBPC3c.1458-1G&gt;A or c.3331-1G&gt;A were analyzed. Haplotype reconstruction was performed to assess a possible founder effect and estimate the approximate age of the shared ancestral allele. Functional characterization was carried out by RNA sequencing of myocardial tissue to evaluate the impact of the variants on splicing. Clinical and phenotypic data were compared with those of carriers of other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Results: Both variants, classified as pathogenic according to ACMG criteria, shared a conserved variant-specific core haplotype. Founder age was estimated at approximately 10.5 generations (~262 years), consistent with a regional founder effect. RNA sequencing demonstrated aberrant splicing for both variants, resulting in premature termination codons and presumably subsequent nonsense-mediated mRNA decay. Clinically, carriers showed delayed disease onset, with a mean onset in the fifth decade of life, and a comparatively milder phenotype, including a lower incidence of sudden cardiac death, than patients carrying other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Both variants exhibited partial penetrance (approximately 63\u201367%) and age-dependent variable expressivity. Conclusions:MYBPC3 c.1458-1G&gt;A and c.3331-1G&gt;A represent novel founder alleles associated with HCM in Northern Italy. Identification of these locally prevalent variants improves molecular diagnosis, family screening, and supports the development of variant-targeted therapeutic approaches.<\/jats:p>","DOI":"10.3390\/genes17080882","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:57:28Z","timestamp":1785254248000},"page":"882","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical, Transcriptional and Haplotype Characterization of Recurrent MYBPC3 Splice-Site Variants c.1458-1G&gt;A and c.3331-1G&gt;A Associated with Hypertrophic Cardiomyopathy in Northern Italy"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1428-8714","authenticated-orcid":false,"given":"Carlotta Pia","family":"Cristalli","sequence":"first","affiliation":[{"name":"SSD Biologia e Medicina Molecolare, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6644-9822","authenticated-orcid":false,"given":"Maria Alessandra","family":"Schiavo","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Cardiac Thoracic and Vascular Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0335-5862","authenticated-orcid":false,"given":"Miryam Rosa Stella","family":"Foti","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0036-8240","authenticated-orcid":false,"given":"Sara","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5934-3030","authenticated-orcid":false,"given":"Federica","family":"Isidori","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2056-1660","authenticated-orcid":false,"given":"Alice","family":"Margutti","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierluigi","family":"Laricchiuta","sequence":"additional","affiliation":[{"name":"SSD Biologia e Medicina Molecolare, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Governatori","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Lai","sequence":"additional","affiliation":[{"name":"Unit of Cardiology, Bentivoglio Hospital, 40010 Bentivoglio, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Uliana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1412-4747","authenticated-orcid":false,"given":"Federico","family":"Barocelli","sequence":"additional","affiliation":[{"name":"Unit of Cardiology, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9211-0810","authenticated-orcid":false,"given":"Elia","family":"De Maria","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Ramazzini Hospital, Carpi, 41012 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1843-2923","authenticated-orcid":false,"given":"Alessandro","family":"Fucili","sequence":"additional","affiliation":[{"name":"Cardiology Department, University Hospital S.Anna Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9028-7169","authenticated-orcid":false,"given":"Biagio","family":"Sassone","sequence":"additional","affiliation":[{"name":"Cardiology Unit, SS.ma Annunziata Hospital, Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Parmeggiani","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Clinical Pathology, AUSL Romagna, 48121 Cesena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrica","family":"Perugini","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Maggiore Hospital, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Lucca","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Cappuccini","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8111-563X","authenticated-orcid":false,"given":"Laura","family":"Pezzoli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-212X","authenticated-orcid":false,"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8569-247X","authenticated-orcid":false,"given":"Maria","family":"Piane","sequence":"additional","affiliation":[{"name":"Sant\u2019Andrea University Hospital, 00189 Rome, Italy"},{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Vitale","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Ospedale Santa Maria Della Scaletta, 40026 Imola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3875-6869","authenticated-orcid":false,"given":"Claudio","family":"Graziano","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Clinical Pathology, AUSL Romagna, 48121 Cesena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3099-0100","authenticated-orcid":false,"given":"Rita","family":"Selvatici","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-9870","authenticated-orcid":false,"given":"Alessandra","family":"Ferlini","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalena","family":"Graziosi","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Cardiac Thoracic and Vascular Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Biagini","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Cardiac Thoracic and Vascular Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), 1105 Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6792-3921","authenticated-orcid":false,"given":"Daniela","family":"Turchetti","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9551-057X","authenticated-orcid":false,"given":"Francesca","family":"Gualandi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences and Department of Mother and Child, University Hospital S. Anna Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1826-615X","authenticated-orcid":false,"given":"Cesare","family":"Rossi","sequence":"additional","affiliation":[{"name":"SSD Biologia e Medicina Molecolare, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","article-title":"2023 ESC Guidelines for the Management of Cardiomyopathies","volume":"44","author":"Arbelo","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1016\/S0140-6736(21)01205-8","article-title":"Hypertrophic Cardiomyopathy: A Practical Approach to Guideline Directed Management","volume":"398","author":"Ommen","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.jacc.2024.12.010","article-title":"Genes Associated with Hypertrophic Cardiomyopathy","volume":"85","author":"Hespe","year":"2025","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Glava\u0161ki, M., Velicki, L., and Vu\u010dini\u0107, N. (2023). Hypertrophic Cardiomyopathy: Genetic Foundations, Outcomes, Interconnections, and Their Modifiers. Medicina, 59.","DOI":"10.3390\/medicina59081424"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Caputo, V., Visconti, V.V., Marchionni, E., Ferradini, V., Balsano, C., De Vico, P., Cal\u00f2, L., Mango, R., Novelli, G., and Sangiuolo, F. (2025). The Diagnostic Value of Copy Number Variants in Genetic Cardiomyopathies and Channelopathies. J. Cardiovasc. Dev. Dis., 12.","DOI":"10.3390\/jcdd12070258"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bonaventura, J., Polakova, E., Vejtasova, V., and Veselka, J. (2021). Genetic Testing in Patients with Hypertrophic Cardiomyopathy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910401"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.pcad.2023.04.009","article-title":"Evolution of Genetic Testing and Gene Therapy in Hypertrophic Cardiomyopathy","volume":"80","author":"Chiswell","year":"2023","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.gene.2015.09.008","article-title":"Cardiac Myosin-Binding Protein C (MYBPC3) in Cardiac Pathophysiology","volume":"573","author":"Carrier","year":"2015","journal-title":"Gene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1136\/jmedgenet-2014-102923","article-title":"A Founder MYBPC3 Mutation Results in HCM with a High Risk of Sudden Death after the Fourth Decade of Life","volume":"52","author":"Calore","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"601","DOI":"10.2459\/01.JCM.0000237908.26377.d6","article-title":"A Molecular Screening Strategy Based on \u03b2-Myosin Heavy Chain, Cardiac Myosin Binding Protein C and Troponin T Genes in Italian Patients with Hypertrophic Cardiomyopathy","volume":"7","author":"Girolami","year":"2006","journal-title":"J. Cardiovasc. 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Aging"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/882\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:59:19Z","timestamp":1785254359000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/882"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":24,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080882"],"URL":"https:\/\/doi.org\/10.3390\/genes17080882","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]}}}