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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2015

Open Access 01-12-2015 | Research

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

Authors: Laurence Campens, Bert Callewaert, Laura Muiño Mosquera, Marjolijn Renard, Sofie Symoens, Anne De Paepe, Paul Coucke, Julie De Backer

Published in: Orphanet Journal of Rare Diseases | Issue 1/2015

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Abstract

Background

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 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.

Methods

We 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.

Results

A 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.

Conclusion

NGS 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.
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Literature
1.
Olsson C, Thelin S, Stahle E, Ekbom A, Granath F. Thoracic aortic aneurysm and dissection: increasing prevalence and improved outcomes reported in a nationwide population-based study of more than 14,000 cases from 1987 to 2002. Circulation. 2006;114:2611–8.CrossRefPubMed
2.
Hoyert DL, Arias E, Smith BL, Murphy SL, Kochanek KD. Deaths: final data for 1999. Natl Vital Stat Rep. 2001;49:1–113.
3.
Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476–85.CrossRefPubMed
4.
Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81.CrossRefPubMed
5.
Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004;36:855–60.CrossRefPubMedCentralPubMed
6.
Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–98.CrossRefPubMed
7.
8.
Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L, et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 2012;44:916–21.CrossRefPubMedCentralPubMed
9.
Renard M, Callewaert B, Malfait F, Campens L, Sharif S, Del Campo M, et al. Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2. Int J Cardiol. 2012;65:584–7.
10.
Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012;44:922–7.CrossRefPubMedCentralPubMed
11.
van der Linde D, Verhagen HJ, Moelker A, van de Laar IM, Van Herzeele I, De Backer J, et al. Aneurysm-osteoarthritis syndrome with visceral and iliac artery aneurysms. J Vasc Surg. 2013;57:96–102.CrossRefPubMedCentralPubMed
12.
van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-Zeinstra SM, et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2012;49:47–57.CrossRefPubMed
13.
van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121–6.CrossRefPubMed
14.
van der Linde D, van de Laar IM, Bertoli-Avella AM, Oldenburg RA, Bekkers JA, Mattace-Raso FU, et al. Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J Am Coll Cardiol. 2012;60:397–403.CrossRefPubMed
15.
Mortani Barbosa EJJ, Pyeritz RE, Litt H, Desjardins B. Vascular Ehlers-Danlos syndrome presenting as rapidly progressive multiple arterial aneurysms and dissections. Am J Med Genet. 2011;155A:3090–4.CrossRefPubMed
16.
Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673–80.CrossRefPubMed
17.
Beighton P, De PA, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77:31–7.CrossRefPubMed
18.
Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39:1488–93.CrossRefPubMed
19.
Renard M, Callewaert B, Baetens M, Campens L, Macdermot K, Fryns JP, et al. Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFbeta signaling in FTAAD. Int J Cardiol. 2013;165:314–21.CrossRefPubMedCentralPubMed
20.
Morisaki H, Akutsu K, Ogino H, Kondo N, Yamanaka I, Tsutsumi Y, et al. Mutation of ACTA2 gene as an important cause of familial and nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection (TAAD). Hum Mutat. 2009;30:1406–11.CrossRefPubMed
21.
Pannu H, Tran-Fadulu V, Papke CL, Scherer S, Liu Y, Presley C, et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16:2453–62.CrossRefPubMedCentralPubMed
22.
Guo DC, Regalado E, Casteel DE, Santos-Cortez RL, Gong L, Kim JJ, et al. Recurrent Gain-of-Function Mutation in PRKG1 Causes Thoracic Aortic Aneurysms and Acute Aortic Dissections. Am J Hum Genet. 2013;93:398–404.CrossRefPubMedCentralPubMed
23.
Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E, et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010;87:701–7.CrossRefPubMedCentralPubMed
24.
Milewicz DM, Regalado E. Thoracic Aortic Aneurysms and Aortic Dissections. 2003 Feb 13 [Updated 2012 Jan 12]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​books/​NBK1120/​
25.
Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, et al. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009;84:617–27.CrossRefPubMedCentralPubMed
26.
Milewicz DM, Ostergaard JR, Ala-Kokko LM, Khan N, Grange DK, Mendoza-Londono R, et al. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet. 2010;152A:2437–43.CrossRefPubMedCentralPubMed
27.
Munot P, Saunders DE, Milewicz DM, Regalado ES, Ostergaard JR, Braun KP, et al. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012;135:2506–14.CrossRefPubMedCentralPubMed
28.
Baetens M, Van Laer L, De Leeneer K, Hellemans J, De Schrijver J, Van De Voorde H, et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat. 2011;32:1053–62.CrossRefPubMed
29.
Collod-Beroud G, Le BS, Ades L, Ala-Kokko L, Booms P, Boxer M, et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2013;22:199–208.CrossRef
30.
Robinson DO, Lin F, Lyon M, Raponi M, Cross E, White HE, et al. Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities. Clin Genet. 2012;82:223–31.CrossRefPubMed
31.
Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001;161:2447–54.CrossRefPubMed
32.
Comeglio P, Johnson P, Arno G, Brice G, Evans A, Aragon-Martin J, et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007;28:928.CrossRefPubMed
33.
Turner CL, Emery H, Collins AL, Howarth RJ, Yearwood CM, Cross E, et al. Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy. Am J Med Genet. 2009;149A:161–70.CrossRefPubMed
34.
Lee Y-J, Yum M-S, Kim E-H, Choi H-W, Lee BH, Yoo H-W, et al. Neurovascular Manifestation of Loeys-Dietz Syndrome: A Case Report. J Genet Med. 2013;10:47–51.CrossRef
35.
Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E, et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation. 2005;112:513–20.CrossRefPubMed
36.
Arno G, Aragon-Martin JA, Song O, Kamali P, Saggar A, Jahangiri M, Child A Mutations in SMAD3 in a British cohort of thoracic aortic aneurysm and dissection (TAAD) patients. Am Soc Hum Gen. 2012 [Abstract]
37.
Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, et al. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011;109:680–6.CrossRefPubMedCentralPubMed
38.
Hoffjan S, Waldmuller S, Blankenfeldt W, Kotting J, Gehle P, Binner P, et al. Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2011;19:520–4.CrossRefPubMedCentralPubMed
39.
Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, and Byers PH. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet Med. 2014 [Epub ahead of print].
40.
Katz DJ, Stanley JC, Zelenock GB. Gender differences in abdominal aortic aneurysm prevalence, treatment, and outcome. J Vasc Surg. 1997;25:561–8.CrossRefPubMed
41.
Harris KM, Strauss CE, Eagle KA, Hirsch AT, Isselbacher EM, Tsai TT, et al. Correlates of delayed recognition and treatment of acute type A aortic dissection: the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2011;124:1911–8.CrossRefPubMed
42.
Stramba-Badiale M, Fox KM, Priori SG, Collins P, Daly C, Graham I, et al. Cardiovascular diseases in women: a statement from the policy conference of the European Society of Cardiology. Eur Heart J. 2006;27:994–1005.CrossRefPubMed
43.
Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A. Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation. 1996;94:2708–11.CrossRefPubMed
44.
Lerner-Ellis JP, Aldubayan SH, Hernandez AL, Kelly MA, Stuenkel AJ, Walsh J, et al. The spectrum of FBN1, TGFbetaR1, TGFbetaR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). Mol Genet Metab. 2014;112:171–6.CrossRefPubMed
45.
Morissette R, Schoenhoff F, Xu Z, Shilane DA, Griswold BF, Chen W, et al. Transforming growth factor-beta and inflammation in vascular (type IV) Ehlers-Danlos syndrome. Circ Cardiovasc Genet. 2014;7:80–8.CrossRefPubMed
46.
Leistritz DF, Pepin MG, Schwarze U, Byers PH. COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy. Genet Med. 2011;13:717–22.CrossRefPubMed
47.
Schwarze U, Schievink WI, Petty E, Jaff MR, Babovic-Vuksanovic D, Cherry KJ, et al. Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV. Am J Hum Genet. 2001;69:989–1001.CrossRefPubMedCentralPubMed
48.
Shalhub S, Black III JH, Cecchi AC, Xu Z, Griswold BF, Safi HJ, et al. Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes. J Vasc Surg. 2014;60:160–9.CrossRefPubMed
49.
Erbel R, Aboyans V, Boileau C, Bossone E, Di Bartolomeo R, Eggebrecht et al. ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014 [Epub ahead of print].
50.
Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey Jr DE, et al. ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010;121:e266–369.CrossRefPubMed
Metadata
Title
Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients
Authors
Laurence Campens
Bert Callewaert
Laura Muiño Mosquera
Marjolijn Renard
Sofie Symoens
Anne De Paepe
Paul Coucke
Julie De Backer
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2015
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-014-0221-6

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