{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:19:50Z","timestamp":1790961590836,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T00:00:00Z","timestamp":1536105600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2018,9,5]]},"abstract":"<jats:p><jats:italic>Background. <\/jats:italic>Bicuspid aortic valve (BAV) is a common congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant pattern of inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with other clinical manifestations in syndromic conditions. Identification of a syndromic condition in a BAV patient is clinically relevant in order to personalize indication to aortic surgery. We aimed to point out how genetic diagnosis by next-generation sequencing (NGS) can improve management of a patient with complex BAV clinical picture.<jats:italic> Methods and Results. <\/jats:italic>We describe a 45-year-old Caucasian male with BAV, thoracic aortic root and ascending aorta dilatation, and connective features evocative but inconclusive for clinical diagnosis of Marfan syndrome (MFS). Targeted (91 genes) NGS was used. Proband genetic variants were investigated in first-degree relatives. Proband carried 5 rare variants in 4 genes:<jats:italic> FBN1<\/jats:italic>(p.Asn542Ser and p.Lys2460Arg),<jats:italic> NOTCH1<\/jats:italic>(p.Val1739Met),<jats:italic> LTBP1<\/jats:italic>(p.Arg1330Gln), and<jats:italic> TGFBR3<\/jats:italic>(p.Arg423Trp). The two FBN1 variants were inherited in cis by the mother, showing systemic features evocative of MFS, but with a milder phenotype than that observed in the proband. Careful clinical observation along with the presence of the<jats:italic> FBN1 <\/jats:italic>variants allowed diagnosis of MFS in the proband and in his mother.<jats:italic> NOTCH1 <\/jats:italic>variant was found in mother and brother, not exhibiting BAV, thus not definitely supporting\/excluding association with BAV. Interestingly, the proband, his brother and father, all showing root dilatation, and his sister, with upper range aortic root dimension, were carriers of a<jats:italic> TGFBR3 <\/jats:italic>variant.<jats:italic> LTBP1<\/jats:italic> might also modulate the vascular phenotype.<jats:italic> Conclusions. <\/jats:italic>Our results underline the usefulness of NGS together with family evaluation in diagnosis of patients with monogenic traits and overlapping clinical manifestations due to contribution of the same genes and\/or presence of comorbidities determined by different genes.<\/jats:p>","DOI":"10.1155\/2018\/8386123","type":"journal-article","created":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T19:33:51Z","timestamp":1536176031000},"page":"1-9","source":"Crossref","is-referenced-by-count":16,"title":["Bicuspid Aortic Valve: Role of Multiple Gene Variants in Influencing the Clinical Phenotype"],"prefix":"10.1155","volume":"2018","author":[{"given":"Elena","family":"Sticchi","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy"},{"name":"Marfan Syndrome and Related Disorders Regional Referral Center, Careggi Hospital, Florence, Italy"},{"name":"Excellence Centre for Research, Transfer and High Education for the Development of De Novo Therapies (DENOTHE), University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8376-2523","authenticated-orcid":true,"given":"Rosina","family":"De Cario","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Magi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-326X","authenticated-orcid":true,"given":"Sabrina","family":"Giglio","sequence":"additional","affiliation":[{"name":"Department of Biomedical Experimental and Clinical Sciences 'Mario Serio', University of Florence, Italy"},{"name":"Medical Genetic Unit, Meyer Children's University Hospital, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldesia","family":"Provenzano","sequence":"additional","affiliation":[{"name":"Department of Biomedical Experimental and Clinical Sciences 'Mario Serio', University of Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Nistri","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy"},{"name":"Cardiology Service, CMSR Veneto Medica, Altavilla Vicentina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guglielmina","family":"Pepe","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy"},{"name":"Marfan Syndrome and Related Disorders Regional Referral Center, Careggi Hospital, Florence, Italy"},{"name":"Excellence Centre for Research, Transfer and High Education for the Development of De Novo Therapies (DENOTHE), University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8708-9444","authenticated-orcid":true,"given":"Betti","family":"Giusti","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Italy"},{"name":"Marfan Syndrome and Related Disorders Regional Referral Center, Careggi Hospital, Florence, Italy"},{"name":"Excellence Centre for Research, Transfer and High Education for the Development of De Novo Therapies (DENOTHE), University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1207059"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.007851"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/196037"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000000031"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/180297"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.03.050"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.17987\/icfj.v1i4.45"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.072785"},{"key":"9","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000312"},{"key":"10","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu281"},{"key":"11","doi-asserted-by":"publisher","DOI":"10.1038\/nature03940"},{"issue":"1","key":"12","volume":"7","year":"2014","journal-title":"BMC Medical Genomics"},{"issue":"1","key":"13","volume":"14","year":"2013","journal-title":"BMC Medical Genetics"},{"key":"14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.07.037"},{"key":"15","doi-asserted-by":"publisher","DOI":"10.1007\/s11886-014-0487-2"},{"key":"16","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2014.67"},{"key":"17","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2015.10.058"},{"issue":"1","key":"18","volume":"15","year":"2014","journal-title":"BMC Medical Genetics"},{"key":"19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2011.12.009"},{"key":"20","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-5223(03)00398-2"},{"key":"21","first-page":"II329","volume":"108","year":"2003","journal-title":"Circulation"},{"key":"22","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2013-304920"},{"key":"23","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2005.04.051"},{"key":"24","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehm528"},{"key":"25","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(89)90430-X"},{"key":"26","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2012.05.063"},{"key":"27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"28","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"30","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq330"},{"key":"31","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199907013410101"},{"key":"32","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4889(00)00085-9"},{"key":"33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2011.01781.x"},{"key":"34","doi-asserted-by":"publisher","DOI":"10.1089\/gte.2006.0514"},{"key":"35","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-014-0221-6"},{"key":"36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.03.045"},{"key":"37","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b00456"},{"key":"38","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.23385"},{"key":"39","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.073437"},{"key":"40","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5410.2080"},{"key":"41","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2008.062844"},{"key":"42","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.009762"},{"key":"43","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2010.12.060"},{"key":"44","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31872"},{"key":"45","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2008.04.044"},{"key":"46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ehj.2003.08.020"},{"key":"47","doi-asserted-by":"publisher","DOI":"10.1067\/mva.2000.107563"},{"issue":"4","key":"48","first-page":"350","volume":"94","year":"2009","journal-title":"International Surgery"},{"key":"49","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5007"},{"key":"50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2005.05.044"},{"key":"51","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.112.000034"},{"key":"52","doi-asserted-by":"publisher","DOI":"10.1007\/s10897-016-0002-6"},{"key":"53","volume":"8","year":"2017","journal-title":"Frontiers in Physiology"}],"container-title":["BioMed Research International"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2018\/8386123.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2018\/8386123.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2018\/8386123.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T19:33:53Z","timestamp":1536176033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.hindawi.com\/journals\/bmri\/2018\/8386123\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,5]]},"references-count":53,"alternative-id":["8386123","8386123"],"URL":"https:\/\/doi.org\/10.1155\/2018\/8386123","relation":{},"ISSN":["2314-6133","2314-6141"],"issn-type":[{"value":"2314-6133","type":"print"},{"value":"2314-6141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,5]]}}}