{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T22:31:39Z","timestamp":1781562699846,"version":"3.54.5"},"reference-count":37,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Association Fran\u00e7aise contre les Myopathies-AFM Telethon","award":["#23408"],"award-info":[{"award-number":["#23408"]}]},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","award":["#23408"],"award-info":[{"award-number":["#23408"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitral valve prolapse (MVP) is a common valvular heart defect with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. Herein, we report a clinical and genetic investigation of a family with bileaflet MVP and a history of syncopes and resuscitated sudden cardiac death. Using family based whole exome sequencing, we identified two missense variants in the SCN5A gene. A rare variant SCN5A:p.Ala572Asp and the well-known functional SCN5A:p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father and sister carried only the SCN5A:p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as the potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and\/or SCD history.<\/jats:p>","DOI":"10.3390\/ijms232214447","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T03:05:11Z","timestamp":1668999911000},"page":"14447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SCN5A Variants as Genetic Arrhythmias Triggers for Familial Bileaflet Mitral Valve Prolapse"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6806-0072","authenticated-orcid":false,"given":"Hager","family":"Jaouadi","sequence":"first","affiliation":[{"name":"Marseille Medical Genetics, INSERM, Aix Marseille Universit\u00e9, U1251 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9453-9039","authenticated-orcid":false,"given":"Alexis","family":"Th\u00e9ron","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics, INSERM, Aix Marseille Universit\u00e9, U1251 Marseille, France"},{"name":"Department of Cardiac Surgery, La Timone Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Hourdain","sequence":"additional","affiliation":[{"name":"Department of Cardiology, La Timone Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Martel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, La Timone Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics, INSERM, Aix Marseille Universit\u00e9, U1251 Marseille, France"},{"name":"Department of Medical Genetics, Timone Enfant Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja","family":"Habachi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, La Timone Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"Deharo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, La Timone Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4247-7184","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Collart","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, La Timone Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Avierinos","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics, INSERM, Aix Marseille Universit\u00e9, U1251 Marseille, France"},{"name":"Department of Cardiology, La Timone Hospital, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-418X","authenticated-orcid":false,"given":"St\u00e9phane","family":"Zaffran","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics, INSERM, Aix Marseille Universit\u00e9, U1251 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1161\/CIRCULATIONAHA.113.006702","article-title":"Epidemiology and pathophysiology of mitral valve prolapse: New insights into disease progression, genetics, and molecular basis","volume":"129","author":"Delling","year":"2014","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"D1","DOI":"10.1530\/ERP-15-0020","article-title":"Sudden cardiac arrest and coexisting mitral valve prolapse: A case report and literature review","volume":"3","author":"Ahmed","year":"2016","journal-title":"Echo Res. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kukavica, D., Guglielmo, M., Baggiano, A., Muscogiuri, G., Fusini, L., Muratori, M., Tamborini, G., Mantegazza, V., Trancuccio, A., and Arn\u00f2, C. (2021). Arrhythmic Mitral Valve Prolapse: Introducing an Era of Multimodality Imaging-Based Diagnosis and Risk Stratification. Diagnostics, 11.","DOI":"10.3390\/diagnostics11030467"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.pcad.2017.10.007","article-title":"Mitral Valve Prolapse: Multimodality Imaging and Genetic Insights","volume":"60","author":"Parwani","year":"2017","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1093\/eurheartj\/ehac048","article-title":"Mitral valve prolapse: Will genetics finally solve the puzzle?","volume":"43","author":"Trenkwalder","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1080\/14779072.2019.1553619","article-title":"Mitral valve prolapse","volume":"17","author":"Althunayyan","year":"2019","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E77","DOI":"10.1093\/eurheartj\/suab096","article-title":"Mitral valve prolapse with ventricular arrhythmias: Does it carries a worse prognosis?","volume":"23","author":"Coutsoumbas","year":"2021","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1161\/CIRCULATIONAHA.115.016291","article-title":"Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death","volume":"132","author":"Basso","year":"2015","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1161\/CIRCULATIONAHA.118.033488","article-title":"Common Phenotype in Patients With Mitral Valve Prolapse Who Experienced Sudden Cardiac Death","volume":"138","author":"Hourdain","year":"2018","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.jacc.2013.02.060","article-title":"Malignant bileaflet mitral valve prolapse syndrome in patients with otherwise idiopathic out-of-hospital cardiac arrest","volume":"62","author":"Sriram","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1161\/CIRCULATIONAHA.114.012594","article-title":"Familial Clustering of Mitral Valve Prolapse in the Community","volume":"131","author":"Delling","year":"2015","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nature14670","article-title":"Mutations in DCHS1 cause mitral valve prolapse","volume":"525","author":"Durst","year":"2015","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"826","DOI":"10.7326\/0003-4819-97-6-826","article-title":"Inheritance of mitral valve prolapse: Effect of age and sex on gene expression","volume":"97","author":"Devereux","year":"1982","journal-title":"Ann. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1086\/302624","article-title":"Mapping of a first locus for autosomal dominant myxomatous mitral-valve prolapse to chromosome 16p11.2-p12.1","volume":"65","author":"Disse","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1086\/375452","article-title":"A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4","volume":"72","author":"Freed","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1161\/CIRCULATIONAHA.104.516930","article-title":"New locus for autosomal dominant mitral valve prolapse on chromosome 13: Clinical insights from genetic studies","volume":"112","author":"Nesta","year":"2005","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaax0290","DOI":"10.1126\/scitranslmed.aax0290","article-title":"Primary cilia defects causing mitral valve prolapse","volume":"11","author":"Toomer","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1086\/301747","article-title":"Mapping of X-linked myxomatous valvular dystrophy to chromosome Xq28","volume":"62","author":"Kyndt","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1136\/heartjnl-2017-312420","article-title":"Genetics of syndromic and non-syndromic mitral valve prolapse","volume":"104","author":"Rimbert","year":"2018","journal-title":"Heart"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.echo.2014.10.003","article-title":"Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging","volume":"28","author":"Lang","year":"2015","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/ejechocard\/jeq031","article-title":"European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: Mitral and tricuspid regurgitation (native valve disease)","volume":"11","author":"Lancellotti","year":"2010","journal-title":"Eur. J. Echocardiogr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1111\/j.1540-8167.2009.01508.x","article-title":"Genetic modulation of brugada syndrome by a common polymorphism","volume":"20","author":"Lizotte","year":"2009","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1161\/CIRCULATIONAHA.105.601294","article-title":"SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene","volume":"114","author":"Poelzing","year":"2006","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.hrthm.2010.04.014","article-title":"Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation","volume":"7","author":"Tester","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/j.1540-8167.2010.01762.x","article-title":"Mutation-specific effects of polymorphism H558R in SCN5A-related sick sinus syndrome","volume":"21","author":"Gui","year":"2010","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.3389\/fphys.2018.01372","article-title":"SCN5A Variants: Association with Cardiac Disorders","volume":"9","author":"Li","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.mgene.2015.07.010","article-title":"Mutational analysis of SCN5A gene in long QT syndrome","volume":"6","author":"Qureshi","year":"2015","journal-title":"Meta Gene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"344","DOI":"10.2459\/JCM.0000000000000670","article-title":"A common polymorphism in the SCN5A gene is associated with dilated cardiomyopathy","volume":"19","author":"Mazzaccara","year":"2018","journal-title":"J. Cardiovasc. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e003481","DOI":"10.1161\/CIRCGEN.121.003481","article-title":"Novel SCN5A Variant Shows Multiple Phenotypic Expression in the Same Family","volume":"14","author":"Balla","year":"2021","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1016\/j.amjmed.2015.05.030","article-title":"Sudden cardiac death, mitral valve prolapse, and long QT syndrome","volume":"128","author":"Missov","year":"2015","journal-title":"Am. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jaccas.2020.11.046","article-title":"Sudden Cardiac Arrest in a Patient With Mitral Valve Prolapse and LMNA and SCN5A Mutations","volume":"3","author":"Mahajan","year":"2021","journal-title":"JACC Case Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.jacep.2018.03.006","article-title":"Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy","volume":"4","author":"Wilde","year":"2018","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1161\/CIRCULATIONAHA.107.736330","article-title":"Cardiac sodium channel gene variants and sudden cardiac death in women","volume":"117","author":"Albert","year":"2008","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5390","DOI":"10.21037\/jtd.2017.11.14","article-title":"Mitral valve prolapse: An underestimated cause of sudden cardiac death\u2014A current review of the literature","volume":"9","author":"Spartalis","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1161\/CIRCULATIONAHA.115.017979","article-title":"The Knot That Binds Mitral Valve Prolapse and Sudden Cardiac Death","volume":"132","author":"Noseworthy","year":"2015","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.hrthm.2015.09.026","article-title":"Mitral valve prolapse and sudden cardiac arrest in the community","volume":"13","author":"Narayanan","year":"2016","journal-title":"Heart Rhythm"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s10554-009-9514-6","article-title":"Predictors of ventricular arrhythmias in patients with mitral valve prolapse","volume":"26","author":"Turker","year":"2010","journal-title":"Int. J. Cardiovasc. Imaging"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:35Z","timestamp":1760145755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,21]]},"references-count":37,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214447"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214447","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,21]]}}}