Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections

Aida M. Bertoli-Avella, Elisabeth Gillis, Hiroko Morisaki, Judith M.A. Verhagen, Bianca M. De Graaf, Gerarda Van De Beek, Elena Gallo, Boudewijn P.T. Kruithof, Hanka Venselaar, Loretha A. Myers, Steven Laga, Alexander J. Doyle, Gretchen Oswald, Gert W.A. Van Cappellen, Itaru Yamanaka, Robert M. Van Der Helm, Berna Beverloo, Annelies De Klein, Luba Pardo, Martin LammensChristina Evers, Koenraad Devriendt, Michiel Dumoulein, Janneke Timmermans, Hennie T. Bruggenwirth, Frans Verheijen, Inez Rodrigus, Gareth Baynam, Marlies Kempers, Johan Saenen, Emeline M. Van Craenenbroeck, Kenji Minatoya, Ritsu Matsukawa, Takuro Tsukube, Noriaki Kubo, Robert Hofstra, Marie Jose Goumans, Jos A. Bekkers, Jolien W. Roos-Hesselink, Ingrid M.B.H. Van De Laar, Harry C. Dietz, Lut Van Laer, Takayuki Morisaki, Marja W. Wessels, Bart L. Loeys

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


BACKGROUND Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-β signaling. OBJECTIVES This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands. CONCLUSIONS Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.

Original languageEnglish (US)
Pages (from-to)1324-1336
Number of pages13
JournalJournal of the American College of Cardiology
Issue number13
StatePublished - 2015


  • Gene
  • Loeys-Dietz syndrome
  • TGF-β pathway
  • Thoracic aortic aneurysm

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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