Dataset Information

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.

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.

SUBMITTER: Bertoli-Avella AM

PROVIDER: S-EPMC4380321 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Bertoli-Avella Aida M AM Gillis Elisabeth E Morisaki Hiroko H Verhagen Judith M A JMA de Graaf Bianca M BM van de Beek Gerarda G Gallo Elena E Kruithof Boudewijn P T BPT Venselaar Hanka H Myers Loretha A LA Laga Steven S Doyle Alexander J AJ Oswald Gretchen G van Cappellen Gert W A GWA Yamanaka Itaru I van der Helm Robert M RM Beverloo Berna B de Klein Annelies A Pardo Luba L Lammens Martin M Evers Christina C Devriendt Koenraad K Dumoulein Michiel M Timmermans Janneke J Bruggenwirth Hennie T HT Verheijen Frans F Rodrigus Inez I Baynam Gareth G Kempers Marlies M Saenen Johan J Van Craenenbroeck Emeline M EM Minatoya Kenji K Matsukawa Ritsu R Tsukube Takuro T Kubo Noriaki N Hofstra Robert R Goumans Marie Jose MJ Bekkers Jos A JA Roos-Hesselink Jolien W JW van de Laar Ingrid M B H IMBH Dietz Harry C HC Van Laer Lut L Morisaki Takayuki T Wessels Marja W MW Loeys Bart L BL

Journal of the American College of Cardiology 20150401 13

<h4>Background</h4>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.<h4>Objectives</h4>This study sought to discover a novel gene causing syndromic aortic aneurysms in order to u ...[more]

PMID: 25835445

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Project description:BackgroundThoracic aortic aneurysms and dissections (TAAD) is a critical condition that often goes undiagnosed with fatal consequences. While majority of the cases are sporadic, more than 20% are inherited as a single gene disorder. The most common familial TAA is Marfan syndrome (MFS), which is primarily caused by mutations in fibrillin-1 (FBN1) gene. Patients with FBN1 mutations are at higher risk for dissection compared to other patients with similar size aneurysms.MethodsFifteen family members were genotyped using Affymetrix-10K genechips. A genome-wide association study was carried out using an autosomal dominant model of inheritance with incomplete penetrance. Mutation screening of all exons and exon-intron boundaries of FBN1 gene which reside near the peak Lod score was carried out by direct sequencing.ResultsThe index case presented with agonizing substernal pain and was found to have TAAD by transthoracic echocardiogram. The family history was significant for 3 first degree relatives with TAA. Nine additional family members were diagnosed with TAA by echocardiography examinations. The affected individuals had no syndromic features. A genome-wide analysis of linkage mapped the disease gene to a single locus on chromosome 15q21 with a peak Lod score of 3.6 at fibrillin-1 (FBN1) gene locus (odds ratio > 4000:1 in favour of linkage), strongly suggesting that FBN1 is the causative gene. No mutation was identified within the exons and exon-intron boundaries of FBN1 gene that segregated with the disease. Haplotype analysis identified additional mutation carriers who had previously unknown status due to borderline dilation of the ascending aorta.ConclusionsA familial non-syndromic TAAD is strongly associated with the FBN1 gene locus and has a malignant disease course often seen in MFS patients. This finding indicates the importance of obtaining detailed family history and echocardiographic screening of extended relatives of patients with non-syndromic TAAD to improve the outcome. In addition, association of non-syndromic TAAD with the Marfan disease gene locus poses the question whether secondary prevention strategies employed for Marfan syndrome patients should be applied to all patients with familial TAAD.

Dataset Information

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

Background

Objectives

Methods

Results

Conclusions

Publications

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

Similar Datasets

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