Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections

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

doi:10.1016/j.jacc.2015.01.040

Abstract

BackgroundAneurysms 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. ObjectivesThis study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. MethodsWe 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. ResultsHere, 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. ConclusionsOur 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.

Highlights

Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture
With the discovery of dysregulated transforming growth factor (TGF)-b signaling in Fbn1 knockout mice, the TGF-b pathway was revealed as a key player in the pathogenesis of thoracic aortic aneurysm development in Marfan syndrome
TAAD = thoracic aortic aneurysms and dissections we report that TGFB3 mutations cause a syndromic form of aortic aneurysms and TGF = transforming growth factor dissections, characterized by cardiovascular, craniofacial, cutaneous, and skeletal anoma