title: Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes.
abstract: At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To circumvent these problems, we developed a TAA gene panel for next-generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation-dependent probe amplification identified large deletions in six of the remaining samples, whereas false-negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Proost
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Vandeweyer
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Josephina A N
authors.initials: JA
authors.lastname: Meester
authors.affiliation: Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Salemink
authors.affiliation: Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marlies
authors.initials: M
authors.lastname: Kempers
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Christie
authors.initials: C
authors.lastname: Ingram
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Nils
authors.initials: N
authors.lastname: Peeters
authors.affiliation: Department of Cardiology, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Saenen
authors.affiliation: Department of Cardiology, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Christiaan
authors.initials: C
authors.lastname: Vrints
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Lacro
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Dan
authors.initials: D
authors.lastname: Roden
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.affiliation: McKusick Nathans Institute for Genetic Medicine, Johns Hopkins University Hospital, Baltimore, Maryland.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.|Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.affiliation: Department of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
mesh_terms: D001014:Aortic Aneurysm / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D009154:Mutation
keywords: Loeys-Dietz syndrome; Marfan syndrome; targeted gene panel; thoracic aortic aneurysm