title: Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: a.bertoliavella@erasmusmc.nl.
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gillis
authors.affiliation: Departments of Bioscience and Genetics, and Medical Genetics, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morisaki
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Judith M A
authors.initials: JMA
authors.lastname: Verhagen
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: de Graaf
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Gerarda
authors.initials: G
authors.lastname: van de Beek
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Elena
authors.initials: E
authors.lastname: Gallo
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Boudewijn P T
authors.initials: BPT
authors.lastname: Kruithof
authors.affiliation: Nijmegen Center for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; Center for Molecular and Biomolecular Informatics (CMBI), Nijmegen, the Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Loretha A
authors.initials: LA
authors.lastname: Myers
authors.affiliation: Department of Cardiac Surgery, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Laga
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Howard Hughes Medical Institute, Baltimore, Maryland; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Doyle
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Howard Hughes Medical Institute, Baltimore, Maryland.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Oswald
authors.affiliation: Erasmus Optical Imaging Centre, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Gert W A
authors.initials: GWA
authors.lastname: van Cappellen
authors.affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Yamanaka
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Robert M
authors.initials: RM
authors.lastname: van der Helm
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Berna
authors.initials: B
authors.lastname: Beverloo
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.affiliation: Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Luba
authors.initials: L
authors.lastname: Pardo
authors.affiliation: Department of Pathology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Evers
authors.affiliation: Center for Human Genetics, Leuven, Belgium.
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Department of Cardiology, AZ Groeninge Kortrijk, Kortrijk, Belgium.
authors.forename: Michiel
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authors.lastname: Dumoulein
authors.affiliation: Department of Cardiology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Hennie T
authors.initials: HT
authors.lastname: Bruggenwirth
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Frans
authors.initials: F
authors.lastname: Verheijen
authors.affiliation: Department of Cardiac Surgery, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Inez
authors.initials: I
authors.lastname: Rodrigus
authors.affiliation: Genetic Services of Western Australia, Subiaco, Western Australia, Australia; School of Paediatrics and Child Health, The University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Gareth
authors.initials: G
authors.lastname: Baynam
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Marlies
authors.initials: M
authors.lastname: Kempers
authors.affiliation: Department of Cardiology, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Saenen
authors.affiliation: Department of Cardiology, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: Emeline M
authors.initials: EM
authors.lastname: Van Craenenbroeck
authors.affiliation: Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Minatoya
authors.affiliation: Department of Cardiovascular Surgery, Japanese Red Cross Kobe Hospital, Kobe, Japan.
authors.forename: Ritsu
authors.initials: R
authors.lastname: Matsukawa
authors.affiliation: Department of Cardiovascular Surgery, Japanese Red Cross Kobe Hospital, Kobe, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Tsukube
authors.affiliation: Department of Pediatrics, Urakawa Red Cross Hospital, Urakawa, Hokkaido, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kubo
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Hofstra
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marie Jose
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: Department of Cardio-Thoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Jos A
authors.initials: JA
authors.lastname: Bekkers
authors.affiliation: Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Jolien W
authors.initials: JW
authors.lastname: Roos-Hesselink
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Ingrid M B H
authors.initials: IMBH
authors.lastname: van de Laar
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Howard Hughes Medical Institute, Baltimore, Maryland; Department of Pediatrics, Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.affiliation: Departments of Bioscience and Genetics, and Medical Genetics, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan; Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Marja W
authors.initials: MW
authors.lastname: Wessels
authors.affiliation: Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address: Bart.Loeys@uantwerp.be.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
mesh_terms: D000328:Adult; D000368:Aged; D000784:Aortic Dissection / Q000235:genetics*; D001014:Aortic Aneurysm / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D053782:Transforming Growth Factor beta3 / Q000235:genetics*
chemical_list: D053782:Transforming Growth Factor beta3
keywords: Loeys-Dietz syndrome; TGF-β pathway; gene; thoracic aortic aneurysm
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