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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

Laurence Campens (UGent) , Bert Callewaert (UGent) , Laura Muiño Mosquera (UGent) , Marjolijn Renard (UGent) , Sofie Symoens (UGent) , Anne De Paepe (UGent) , Paul Coucke (UGent) and Julie De Backer (UGent)
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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.
Keywords
ARTERIAL ANEURYSMS, VASCULAR TYPE, OF-CARDIOLOGY, FBN1 MUTATIONS, MOLECULAR DIAGNOSIS, MARFAN-SYNDROME, GROWTH-FACTOR-BETA, ANEURYSMS-OSTEOARTHRITIS SYNDROME, SYNDROME TYPE-IV, EHLERS-DANLOS-SYNDROME, mutation detection rate, Dissecting/genetics, Aneurysm, Heritable Thoracic Aortic Disorders, next generation sequencing

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Chicago
Campens, Laurence, Bert Callewaert, Laura Muiño Mosquera, Marjolijn Renard, Sofie Symoens, Anne De Paepe, Paul Coucke, and Julie De Backer. 2015. “Gene Panel Sequencing in Heritable Thoracic Aortic Disorders and Related Entities: Results of Comprehensive Testing in a Cohort of 264 Patients.” Orphanet Journal of Rare Diseases 10.
APA
Campens, L., Callewaert, B., Muiño Mosquera, L., Renard, M., Symoens, S., De Paepe, A., Coucke, P., et al. (2015). Gene panel sequencing in heritable thoracic aortic disorders and related entities: results of comprehensive testing in a cohort of 264 patients. ORPHANET JOURNAL OF RARE DISEASES, 10.
Vancouver
1.
Campens L, Callewaert B, Muiño Mosquera L, Renard M, Symoens S, De Paepe A, et al. Gene panel sequencing in heritable thoracic aortic disorders and related entities: results of comprehensive testing in a cohort of 264 patients. ORPHANET JOURNAL OF RARE DISEASES. 2015;10.
MLA
Campens, Laurence, Bert Callewaert, Laura Muiño Mosquera, et al. “Gene Panel Sequencing in Heritable Thoracic Aortic Disorders and Related Entities: Results of Comprehensive Testing in a Cohort of 264 Patients.” ORPHANET JOURNAL OF RARE DISEASES 10 (2015): n. pag. Print.
@article{5848166,
  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.},
  articleno    = {9},
  author       = {Campens, Laurence and Callewaert, Bert and Muiño Mosquera, Laura and Renard, Marjolijn and Symoens, Sofie and De Paepe, Anne and Coucke, Paul and De Backer, Julie},
  issn         = {1750-1172},
  journal      = {ORPHANET JOURNAL OF RARE DISEASES},
  keywords     = {ARTERIAL ANEURYSMS,VASCULAR TYPE,OF-CARDIOLOGY,FBN1 MUTATIONS,MOLECULAR DIAGNOSIS,MARFAN-SYNDROME,GROWTH-FACTOR-BETA,ANEURYSMS-OSTEOARTHRITIS SYNDROME,SYNDROME TYPE-IV,EHLERS-DANLOS-SYNDROME,mutation detection rate,Dissecting/genetics,Aneurysm,Heritable Thoracic Aortic Disorders,next generation sequencing},
  language     = {eng},
  pages        = {9},
  title        = {Gene panel sequencing in heritable thoracic aortic disorders and related entities: results of comprehensive testing in a cohort of 264 patients},
  url          = {http://dx.doi.org/10.1186/s13023-014-0221-6},
  volume       = {10},
  year         = {2015},
}

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