Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2

Renard, Marjolijn; Callewaert, Bert; Malfait, Fransiska; Campens, Laurence; Sharif, Saba; Campo, Miguel del; Valenzuela, Irene; McWilliam, Catherine; Coucke, Paul; Paepe, Anne De; Backer, Julie De

doi:10.1016/j.ijcard.2012.09.029

Cited by 64 publications

(56 citation statements)

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“…In addition to previously reported FBN1, TGFBR1/2 , TGFB2 , SMAD3 and ACTA2 mutations [9,12,18,19,24,35,43], we report on a COL3A1 mutation in a nonsyndromic H-TAD patient. The mutation detection rate in the FBN1 gene in the nonsyndromic H-TAD patient group (1.9%) is in line with previously published data [44].…”

Section: Discussionsupporting

confidence: 50%

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Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Campens

Callewaert

Mosquera

et al. 2015

Orphanet J Rare Dis

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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.

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Section: Discussionsupporting

confidence: 50%

“…(Arg460His)NS DAD TGFB2 1627c.577C > T*p. (Arg193Trp)S H-TAD1748c.980G > A [9]p. (Arg327Gln)S H-TAD183c.988C > T [10]p.…”

Section: Resultsmentioning

confidence: 99%

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Campens

Callewaert

Mosquera

et al. 2015

Orphanet J Rare Dis

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“…In LDS patients, pulmonary valve stenosis could also develop over time (21). Similar to MFS, MVP and mitral valve insufficiency are more frequently observed than in the general population (27,35), but appear to be somewhat less common in LDS compared to MFS (36).…”

Section: Cardiovascular Featuresmentioning

confidence: 99%

Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome

Meester

Verstraeten

Schepers

et al. 2017

Ann. Cardiothorac. Surg.

228

184

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Many different heritable connective tissue disorders (HCTD) have been described over the past decades.These syndromes often affect the connective tissue of various organ systems, including heart, blood vessels, skin, joints, bone, eyes, and lungs. The discovery of these HCTD was followed by the identification of mutations in a wide range of genes encoding structural proteins, modifying enzymes, or components of the In contrast, no association is reported between LDS and the presence of ectopia lentis, a key distinguishing feature of MFS. Overlapping features between MFS and LDS include scoliosis, pes planus, anterior chest deformity, spontaneous pneumothorax, and dural ectasia. EDS refers to a group of clinically and genetically heterogeneous connective tissue disorders and all subtypes are characterized by variable abnormalities of skin, ligaments and joints, blood vessels, and internal organs. Typical presenting features include joint hypermobility, skin hyperextensibility, and tissue fragility. Up to one quarter of the EDS patients show aortic aneurysmal disease. The latest EDS nosology distinguishes 13 subtypes. Many phenotypic features show overlap between the different subtypes, which makes the clinical diagnosis rather difficult and highlights the importance of molecular diagnostic confirmation.

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“…Abbreviations: LAP -latency associated peptide, LTBP -latent TGFβ-binding protein, P -phosphorylated, others -see at a diameter <50 mm. 4,6,7,15,18,25,27,41,54 There are no clear guidelines concerning the indications for prophylactic surgery in these patients. Prophylactic surgery may be considered if the diameter is above 45 mm in nonsyndromic H-TAD patients with a familial history of aortic dissection at minimal dilatation of the thoracic aorta (<50 mm), in case of rapid growth of the aorta, and in patients who need surgery for aortic valve repair or replacement.…”

Section: Figurementioning

confidence: 99%

“…Mutations in other genes involved in the TGFβ pathway (see below) have been identified including SMAD3 causing AOS, SMAD4, the TGFβ2 ligand TGFβ2, and the TGFβ repressor SKI causing Shprintzen-Goldberg syndrome (SGS). [15][16][17][18][19][20][21][22] In view of the important clinical overlap between these disorders, the term "TGFβ-associated vasculopathies" may be preferred over individual syndrome names. The genetic background of nonsyndromic H-TAD is complex and heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

New insights into the molecular diagnosis and management of heritable thoracic aortic aneurysms and dissections

Campens¹,

Renard²,

Callewaert³

et al. 2013

Polish Archives of Internal Medicine

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Since the identification of the fibrillin-1 gene as the causal gene for Marfan syndrome, our knowledge of molecular genetics and the applicability of genetic testing for heritable thoracic aneurysms and dissections (H-TAD) in clinical practice have increased substantially. Several new syndromes related to H-TAD have been described and the list of mutated genes in syndromal and nonsyndromal H-TAD is rapidly expanding. This knowledge has led to a significant improvement of our insight into the underlying pathophysiology of H-TAD resulting in new opportunities for targeted treatment, as well as in improved risk stratification. Clinicians involved in the care for H-TAD patients require a basic knowledge of the disease entities and need to be correctly informed on the applicability of genetic testing in their patients and families. Gene-tailored treatment and management should now be considered as part of good clinical practice. We provide a systematic overview of genetic H-TAD entities and practical recommendations for genetic testing and patient management.

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Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2

Cited by 64 publications

References 14 publications

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome

New insights into the molecular diagnosis and management of heritable thoracic aortic aneurysms and dissections

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