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TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome


A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations—a frameshift mutation in exon 6 and a nonsense mutation in exon 4—segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

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Figure 1: Identification of TGFB2 as the causative gene in thoracic aortic disease in families TAA288 and MS239.
Figure 2: Transcript and protein analysis of the TGFB2 mutation in exon 6 encoding p.Tyr341Cysfs*25.
Figure 3: Aortic pathology and assessment of TGF-β signaling in individuals with TGFB2 mutations.
Figure 4: Clinical features associated with TGFB2 mutations.

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The authors are extremely grateful to the families involved in this study and to the medical professionals who aided in the collection of clinical data from the families. We would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung Cohorts Sequencing Project (HL-102923), the NHLBI Women's Health Initiative Sequencing Project (HL-102924), the Heart Cohorts Sequencing Project (HL-103010), the Broad Institute Sequencing Project (HL-102925), the Northwest Genomics Center Sequencing Project (HL-102926 to D.A.N., M.J.R. and J.S.) and the Family Studies Project Team. We thank J.M. Serfaty for providing vascular imaging and L. Louedec and Z. Ren for technical assistance.

The following sources provided funding for these studies: the US National Institutes of Health (NIH) RO1 HL62594 (D.M.M.), NIH P50HL083794-01 (D.M.M.), NIH UL1 RR024148 (Centers for Clinical and Translational Sciences), the Vivian L. Smith Foundation (D.M.M.), the TexGen Foundation (D.M.M.), Richard T. Pasani Funds (D.M.M.), Groupement d'Interet Scientifique (GIS)–Maladies Rares (C.B.), Projet Hospitalier de Recherche Clinique (PHRC) AOM09093 (G.J.), PHRC AOM 10108 (C.B.), Agence Nationale de Recherche (ANR) 2010 BLAN 1129 from the French National Research Agency (G.J.) and the European Union Framework Programme 7–integrated project Fighting Aneurysmal Disease (FAD, see URLs) (J.B.M.).

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C.B., D.M.M. and G.J. planned the project, designed the experiments, oversaw all aspects of the research and wrote the manuscript. C.B., S.M.L., R.L.P.S.-C., M.V., D.-C.G., M.-S.G. and M.A. performed linkage analyses and analyzed exome sequencing data. M.J.R., J.S. and D.A.N. performed the exome sequencing in TAA288. D.-C.G., A.H.L. and N.H. analyzed exome sequencing data and performed Sanger sequencing analysis with H.d'I., L.G., D.-C.G. and C.S.K. performed the TGFB2 transcript and protein assays. J.B.M. performed histological and imunostaining analyses with M.-S.G. S.K.P. carried out the genomic deletion analysis. E.S.R., B.G., C.M., A.C.B. and L. Gouya provided clinical and pedigree data. D.D., D.M.M. and G.J. provided clinical data and performed sample collection. A.V. revised the manuscript.

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Correspondence to Catherine Boileau or Dianna M Milewicz.

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Boileau, C., Guo, DC., Hanna, N. et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet 44, 916–921 (2012).

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