{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:14:08Z","timestamp":1759191248998,"version":"3.44.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Joint Funds for the innovation of science and Technology in Fujian province","award":["2023Y9284"],"award-info":[{"award-number":["2023Y9284"]}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2024J011017, 2023J011846, 2024Y0033, 2023J011159, 2021J05075"],"award-info":[{"award-number":["2024J011017, 2023J011846, 2024Y0033, 2023J011159, 2021J05075"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National famous and old Chinese medicine experts (Xuemei Zhang, Xiaohua Yan, Shaoguang Lv) inheritance studio construction project"},{"name":"Fujian Provincial Senior Talent Training Progam on Western Medicine Doctors Learning from Traditional Chinese Medicine"},{"DOI":"10.13039\/501100018534","name":"Medical Innovation Project of Fujian Province","doi-asserted-by":"publisher","award":["2022CXA001"],"award-info":[{"award-number":["2022CXA001"]}],"id":[{"id":"10.13039\/501100018534","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health Commission Science and Technology Program of Fujian","award":["2024GGA090, 2024QNA002"],"award-info":[{"award-number":["2024GGA090, 2024QNA002"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cardiovasc Disord"],"DOI":"10.1186\/s12872-025-05100-0","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T17:11:16Z","timestamp":1759165876000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel NOTCH1 nonsense variant in a bicuspid aortic valve family with intrafamilial clinical heterogeneity"],"prefix":"10.1186","volume":"25","author":[{"given":"Qian","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi-yan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wu","family":"Chi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-qian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan-dan","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong-ping","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei-zhu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-sheng","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhu-ting","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie-wei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"issue":"14","key":"5100_CR1","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1136\/heartjnl-2021-320428","volume":"108","author":"RM Debiec","year":"2022","unstructured":"Debiec RM, Hamby SE, Jones PD, Safwan K, Sosin M, Hetherington SL, et al. Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions. Heart. 2022;108(14):1114\u201320. https:\/\/doi.org\/10.1136\/heartjnl-2021-320428.","journal-title":"Heart"},{"issue":"3","key":"5100_CR2","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/j.ahj.2004.10.036","volume":"150","author":"E Tutar","year":"2005","unstructured":"Tutar E, Ekici F, Atalay S, Nacar N. The prevalence of bicuspid aortic valve in newborns by echocardiographic screening. Am Heart J. 2005;150(3):513\u20135. https:\/\/doi.org\/10.1016\/j.ahj.2004.10.036.","journal-title":"Am Heart J"},{"issue":"7056","key":"5100_CR3","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nature03940","volume":"437","author":"V Garg","year":"2005","unstructured":"Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270\u20134. https:\/\/doi.org\/10.1038\/nature03940.","journal-title":"Nature"},{"key":"5100_CR4","doi-asserted-by":"publisher","first-page":"400","DOI":"10.3389\/fphys.2017.00400","volume":"8","author":"E Gillis","year":"2017","unstructured":"Gillis E, Kumar AA, Luyckx I, Preuss C, Cannaerts E, van de Beek G, et al. Candidate gene resequencing in a large bicuspid aortic Valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor. Front Physiol. 2017;8:400. https:\/\/doi.org\/10.3389\/fphys.2017.00400.","journal-title":"Front Physiol"},{"issue":"1","key":"5100_CR5","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/s41588-018-0265-y","volume":"51","author":"RA Gould","year":"2019","unstructured":"Gould RA, Aziz H, Woods CE, Seman-Senderos MA, Sparks E, Preuss C, et al. ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nat Genet. 2019;51(1):42\u201350. https:\/\/doi.org\/10.1038\/s41588-018-0265-y.","journal-title":"Nat Genet"},{"key":"5100_CR6","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/S0070-2153(10)92011-5","volume":"92","author":"D MacGrogan","year":"2010","unstructured":"MacGrogan D, Nus M, de la Pompa JL. Notch signaling in cardiac development and disease. Curr Top Dev Biol. 2010;92:333\u201365. https:\/\/doi.org\/10.1016\/S0070-2153(10)92011-5.","journal-title":"Curr Top Dev Biol"},{"issue":"10","key":"5100_CR7","doi-asserted-by":"publisher","first-page":"e1437","DOI":"10.1002\/mgg3.1437","volume":"8","author":"R Debiec","year":"2020","unstructured":"Debiec R, Hamby SE, Jones PD, Coolman S, Asiani M, Kharodia S, et al. Novel loss of function mutation in NOTCH1 in a family with bicuspid aortic valve, ventricular septal defect, thoracic aortic aneurysm, and aortic valve stenosis. Mol Genet Genomic Med. 2020;8(10):e1437. https:\/\/doi.org\/10.1002\/mgg3.1437.","journal-title":"Mol Genet Genomic Med"},{"issue":"6","key":"5100_CR8","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1016\/j.cell.2016.08.055","volume":"166","author":"D Srivastava","year":"2016","unstructured":"Srivastava D, DeWitt N. In vivo cellular reprogramming: the next generation. Cell. 2016;166(6):1386\u201396. https:\/\/doi.org\/10.1016\/j.cell.2016.08.055.","journal-title":"Cell"},{"issue":"8","key":"5100_CR9","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1161\/CIRCULATIONAHA.123.065458","volume":"149","author":"Y Lin","year":"2024","unstructured":"Lin Y, Yang Q, Lin X, Liu X, Qian Y, Xu D, et al. Extracellular matrix disorganization caused by ADAMTS16 deficiency leads to bicuspid aortic valve with raphe formation. Circulation. 2024;149(8):605\u201326. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.123.065458.","journal-title":"Circulation"},{"issue":"17","key":"5100_CR10","doi-asserted-by":"publisher","first-page":"11785","DOI":"10.1074\/jbc.M708424200","volume":"283","author":"J Cordle","year":"2008","unstructured":"Cordle J, Redfieldz C, Stacey M, van der Merwe PA, Willis AC, Champion BR, et al. Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity. J Biol Chem. 2008;283(17):11785\u201393. https:\/\/doi.org\/10.1074\/jbc.M708424200.","journal-title":"J Biol Chem"},{"issue":"5","key":"5100_CR11","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1021\/acs.biochem.5b01284","volume":"55","author":"S Hayakawa","year":"2016","unstructured":"Hayakawa S, Koide R, Hinou H, Nishimura S. Synthetic human NOTCH1 EGF modules unraveled molecular mechanisms for the structural and functional roles of calcium ions and O-glycans in the ligand-binding region. Biochemistry. 2016;55(5):776\u201387. https:\/\/doi.org\/10.1021\/acs.biochem.5b01284.","journal-title":"Biochemistry"},{"key":"5100_CR12","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwy106","author":"F Pennarubia","year":"2018","unstructured":"Pennarubia F, Pinault E, Maftah A, Legardinier S. In vitro acellular method to reveal O-fucosylation on EGF-like domains. Glycobiology. 2018. https:\/\/doi.org\/10.1093\/glycob\/cwy106.","journal-title":"Glycobiology"},{"issue":"14","key":"5100_CR13","doi-asserted-by":"publisher","first-page":"8108","DOI":"10.1073\/pnas.95.14.8108","volume":"95","author":"F Logeat","year":"1998","unstructured":"Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A. 1998;95(14):8108\u201312. https:\/\/doi.org\/10.1073\/pnas.95.14.8108.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"5100_CR14","doi-asserted-by":"publisher","first-page":"e10532","DOI":"10.1371\/journal.pone.0010532","volume":"5","author":"DF Kelly","year":"2010","unstructured":"Kelly DF, Lake RJ, Middelkoop TC, Fan HY, Artavanis-Tsakonas S, Walz T. Molecular structure and dimeric organization of the Notch extracellular domain as revealed by electron microscopy. PLoS One. 2010;5(5):e10532. https:\/\/doi.org\/10.1371\/journal.pone.0010532.","journal-title":"PLoS One"},{"issue":"6","key":"5100_CR15","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1016\/j.devcel.2012.04.005","volume":"22","author":"L Meloty-Kapella","year":"2012","unstructured":"Meloty-Kapella L, Shergill B, Kuon J, Botvinick E, Weinmaster G. Notch ligand endocytosis generates mechanical pulling force dependent on dynamin, epsins, and actin. Dev Cell. 2012;22(6):1299\u2013312. https:\/\/doi.org\/10.1016\/j.devcel.2012.04.005.","journal-title":"Dev Cell"},{"issue":"2","key":"5100_CR16","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/s1097-2765(00)80417-7","volume":"5","author":"C Brou","year":"2000","unstructured":"Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000;5(2):207\u201316. https:\/\/doi.org\/10.1016\/s1097-2765(00)80417-7.","journal-title":"Mol Cell"},{"issue":"2","key":"5100_CR17","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","volume":"137","author":"R Kopan","year":"2009","unstructured":"Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216\u201333. https:\/\/doi.org\/10.1016\/j.cell.2009.03.045.","journal-title":"Cell"},{"issue":"6547","key":"5100_CR18","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/377355a0","volume":"377","author":"S Jarriault","year":"1995","unstructured":"Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995;377(6547):355\u20138. https:\/\/doi.org\/10.1038\/377355a0.","journal-title":"Nature"},{"issue":"3","key":"5100_CR19","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1002\/jcp.10208","volume":"194","author":"T Iso","year":"2003","unstructured":"Iso T, Kedes L, Hamamori Y. Hes and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003;194(3):237\u201355. https:\/\/doi.org\/10.1002\/jcp.10208.","journal-title":"J Cell Physiol"},{"issue":"2","key":"5100_CR20","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1042\/BJ20121153","volume":"449","author":"A Sharma","year":"2013","unstructured":"Sharma A, Rangarajan A, Dighe RR. Antibodies against the extracellular domain of human Notch1 receptor reveal the critical role of epidermal-growth-factor-like repeats 25\u201326 in ligand binding and receptor activation. Biochem J. 2013;449(2):519\u201330. https:\/\/doi.org\/10.1042\/BJ20121153.","journal-title":"Biochem J"},{"issue":"1","key":"5100_CR21","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/nrg2279","volume":"9","author":"FA High","year":"2008","unstructured":"High FA, Epstein JA. The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet. 2008;9(1):49\u201361. https:\/\/doi.org\/10.1038\/nrg2279.","journal-title":"Nat Rev Genet"},{"issue":"9","key":"5100_CR22","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1038\/gim.2015.193","volume":"18","author":"WS Kerstjens-Frederikse","year":"2016","unstructured":"Kerstjens-Frederikse WS, van de Laar IM, Vos YJ, Verhagen JM, Berger RM, Lichtenbelt KD, et al. Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families. Genet Med. 2016;18(9):914\u201323. https:\/\/doi.org\/10.1038\/gim.2015.193.","journal-title":"Genet Med"},{"issue":"4","key":"5100_CR23","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1161\/CIRCGENETICS.115.001086","volume":"8","author":"L Southgate","year":"2015","unstructured":"Southgate L, Sukalo M, Karountzos ASV, Taylor EJ, Collinson CS, Ruddy D, et al. Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies. Circ Cardiovasc Genet. 2015;8(4):572\u201381. https:\/\/doi.org\/10.1161\/CIRCGENETICS.115.001086.","journal-title":"Circ Cardiovasc Genet"},{"issue":"10","key":"5100_CR24","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.1172\/JCI42666","volume":"120","author":"L Luna-Zurita","year":"2010","unstructured":"Luna-Zurita L, Prados B, Grego-Bessa J, Luxan G, del Monte G, Benguria A, et al. Integration of a notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation. J Clin Invest. 2010;120(10):3493\u2013507. https:\/\/doi.org\/10.1172\/JCI42666.","journal-title":"J Clin Invest"},{"issue":"1","key":"5100_CR25","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10237-021-01527-4","volume":"21","author":"BJ Vogl","year":"2022","unstructured":"Vogl BJ, Niemi NR, Griffiths LG, Alkhouli MA, Hatoum H. Impact of calcific aortic valve disease on valve mechanics. Biomech Model Mechanobiol. 2022;21(1):55\u201377. https:\/\/doi.org\/10.1007\/s10237-021-01527-4.","journal-title":"Biomech Model Mechanobiol"},{"issue":"6","key":"5100_CR26","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1016\/j.cell.2015.02.035","volume":"160","author":"CV Theodoris","year":"2015","unstructured":"Theodoris CV, Li M, White MP, Liu L, He D, Pollard KS, et al. Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency. Cell. 2015;160(6):1072\u201386. https:\/\/doi.org\/10.1016\/j.cell.2015.02.035.","journal-title":"Cell"},{"issue":"7","key":"5100_CR27","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/s41431-024-01629-4","volume":"32","author":"KJ Stanley","year":"2024","unstructured":"Stanley KJ, Kalbfleisch KJ, Moran OM, Chaturvedi RR, Roifman M, Chen X, et al. Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease. Eur J Hum Genet. 2024;32(7):795\u2013803. https:\/\/doi.org\/10.1038\/s41431-024-01629-4.","journal-title":"Eur J Hum Genet"},{"issue":"1","key":"5100_CR28","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1186\/s13287-018-0945-7","volume":"9","author":"JK Park","year":"2018","unstructured":"Park JK, Lee TW, Do EK, Moon HJ, Kim JH. Role of Notch1 in the arterial specification and angiogenic potential of mouse embryonic stem cell-derived endothelial cells. Stem Cell Res Ther. 2018;9(1):197. https:\/\/doi.org\/10.1186\/s13287-018-0945-7.","journal-title":"Stem Cell Res Ther"},{"issue":"3","key":"5100_CR29","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/s11547-019-01114-9","volume":"125","author":"NM Batouty","year":"2020","unstructured":"Batouty NM, Sobh DM, Gadelhak B, Sobh HM, Mahmoud W, Tawfik AM. Left superior vena cava: cross-sectional imaging overview. Radiol Med. 2020;125(3):237\u201346. https:\/\/doi.org\/10.1007\/s11547-019-01114-9.","journal-title":"Radiol Med"}],"container-title":["BMC Cardiovascular Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-025-05100-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12872-025-05100-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-025-05100-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T17:11:16Z","timestamp":1759165876000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccardiovascdisord.biomedcentral.com\/articles\/10.1186\/s12872-025-05100-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["5100"],"URL":"https:\/\/doi.org\/10.1186\/s12872-025-05100-0","relation":{},"ISSN":["1471-2261"],"issn-type":[{"value":"1471-2261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]},"assertion":[{"value":"24 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures were performed in accordance to the tenets of the Declaration of Helsinki and the study was approved by the Ethics Committee of Fujian Provincial Hospital, Fuzhou, China, with the approval number: K2022-12-009. All participants and legal guardians of the minors involved in the present study provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"706"}}