Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations

Department of Internal Medicine and Department of Neurosurgery, University of Texas Health Science Center at Houston, Texas, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 07/2009; 46(9):607-13. DOI: 10.1136/jmg.2008.062844
Source: PubMed


Mutations in the transforming growth factor beta receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date.
The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing. Clinical features of affected individuals were assessed and compared with clinical features of previously described TGFBR2 families.
Statistical analyses of the clinical features of the TGFBR1 cohort (n = 30) were compared with clinical features of TGFBR2 cohort (n = 77). Significant differences were identified in clinical presentation and survival based on gender in TGFBR1 families but not in TGFBR2 families. In families with TGFBR1 mutations, men died younger than women based on Kaplan-Meier survival curves. In addition, men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. The data also suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters <5.0 cm than individuals with TGFBR1 mutations.
This study is the first to demonstrate clinical differences between patients with TGFBR1 and TGFBR2 mutations. These differences are important for the clinical management and outcome of vascular diseases in these patients.

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    • "Several genes are associated with TAAD including MYH11, ACTA2, SLC2A10, SMAD3, and MYLK [El-Hamamsy and Yacoub, 2009; Regalado et al., 2011]. TAAD can also result from TGFBR1 or TGFBR2 mutations in individuals who do not have the phenotypic features of Loeys– Dietz syndrome [Tran-Fadulu et al., 2009]. Congenital contractural arachnodactyly (CCA), an autosomal dominant disorder caused by fibrillin 2 (FBN2) mutations, is characterized by a Marfan syndrome-like appearance and shares some clinical overlap with MFS as both syndromes can present with skeletal complications including arachnodactyly, dolichostenomelia, pectus deformities , and kyphoscoliosis [Gupta et al., 2004]. "
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    ABSTRACT: Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2015; 167(8). DOI:10.1002/ajmg.a.37085 · 2.16 Impact Factor
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    • "Moreover, FBN1 and TGFBR1/TGFBR2 mutations were shown to lead to a diverging range of phenotypes. For example, mutations in FBN1 as well as TGFBR1 and TGFBR2 have been identified in nonsyndromic TAA [Milewicz et al., 1996; Tran-Fadulu et al., 2009; Keramati et al., 2010], whereas mutations in TGFBR2 have been associated with a MFS-related phenotype [Mizuguchi et al., 2004]. In addition, several new genes have been implicated in the pathogenesis of TAA. "
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    ABSTRACT: At least 14 causative genes have been identified for both syndromic and non-syndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To circumvent these problems, we developed a TAA gene panel for next generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex Ligation-dependent Probe Amplification identified large deletions in 6 of the remaining samples, while false negative results were excluded by Sanger sequencing of FBN1, TGFBR1 and TGFBR2 in the last 4 samples. Subsequently, we screened 55 syndromic and non-syndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the 6 following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), 2 in NOTCH1 and 7 in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 04/2015; 36(8). DOI:10.1002/humu.22802 · 5.14 Impact Factor
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    • "Clinical diagnosis of TAAD can be established using different imaging modalities. Multiple genes and loci have been associated with TAAD including FBN1, TGFβR1, TGFβR2 and MYH11 [19] [20] [21]. In addition, about 14% of TAAD patients were found to have ACTA2 mutations [22]. "
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    ABSTRACT: Introduction In this study, patients suspected of having a clinical diagnosis of Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS) and Thoracic Aortic Aneurysms and dissections (TAAD) were referred for genetic testing and examined for mutations in the FBN1, TGFβR1, TGFβR2 and ACTA2 genes. Methods We examined 594 samples from unrelated individuals and different combinations of genes were sequenced, including one or more of the following: FBN1, TGFβR1, TGFβR2, ACTA2, and, in some cases, FBN1 was analyzed by MLPA to detect large deletions. Results A total of 112 patients had a positive result. Of those, 61 had a clinical diagnosis of MFS, eight had LDS, three had TAAD and 40 patients had clinical features with no specific diagnosis provided. A total of 44 patients had an inconclusive result; 12 patients were referred with a clinical diagnosis of MFS, 4 with LDS and 9 with TAAD and 19 had no clinical diagnosis. A total of 89 mutations were novel. Conclusion This study reveals the rate of detection of variants in several genes associated with MFS, LDS and TAAD. The evaluation of patients by individuals with expertise in the field may decrease the likelihood of ordering unnecessary molecular testing. Nevertheless, genetic testing supports the diagnosis of MFS, LDS and TAAD.
    Molecular Genetics and Metabolism 06/2014; 112(2). DOI:10.1016/j.ymgme.2014.03.011 · 2.63 Impact Factor
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