title: Gene panel sequencing in heritable thoracic aortic disorders and related entities - results of comprehensive testing in a cohort of 264 patients.
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.
  
  
  CONCLUSIONS
  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.
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. laurence.campens@ugent.be.
authors: Laurence
authors: L
authors: Campens
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. bert.callewaert@ugent.be.
authors: Bert
authors: B
authors: Callewaert
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. lmuino@gmail.com.
authors: Laura
authors: L
authors: Muiño Mosquera
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. marjolijn.renard@ugent.be.
authors: Marjolijn
authors: M
authors: Renard
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. sofie.symoens@ugent.be.
authors: Sofie
authors: S
authors: Symoens
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. anne.depaepe@ugent.be.
authors: Anne
authors: A
authors: De Paepe
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. paul.coucke@ugent.be.
authors: Paul
authors: P
authors: Coucke
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185 - 0 K5, 9000, Ghent, Belgium. julie.debacker@ugent.be.|Cardiology Department, Ghent University Hospital, 9000, Ghent, Belgium. julie.debacker@ugent.be.
authors: Julie
authors: J
authors: De Backer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001013:Aorta, Thoracic / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007223:Infant; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D055815:Young Adult
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