Abstract
BackgroundHeritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported.MethodsWe performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative.ResultsA mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS.ConclusionNGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0221-6) contains supplementary material, which is available to authorized users.
Highlights
Heritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated manifestation
For patients referred from outside the Center of Medical Genetics Ghent (CMGG), phenotypic information was provided by the referring physician via a check-list specific for H-TAD (Additional file 1), which included age, gender, suspected diagnosis, specifications regarding aortic/vascular disease and the option to indicate any observed phenotypic feature, including those listed in the revised Ghent nosology, and a pedigree [3]
A causal mutation could be identified in 34 patients (13%): 12 FBN1 (35.3%), one TGFBR1 (2.9%), two TGFBR2 (5.9%), three TGFB2 (8.8%), nine SMAD3 (26.5%), three COL3A1 (8.8%) and four ACTA2 (11.8%) mutations
Summary
Heritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. The etiology of TAD is complex and heterogeneous Both genetic and acquired forms can be distinguished. The genetically determined forms can be categorized into syndromic and nonsyndromic heritable. The diagnosis of MFS is based on the identification of clinical manifestations, as defined in the revised Ghent nosology, and may be supplemented with the identification of an underlying mutation in the FBN1 gene, encoding the fibrillin-1 protein [3]
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