title: Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy.
abstract: Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.|Department of Pathology, University of Utah, Salt Lake City, Utah.
authors.forename: Whitney
authors.initials: W
authors.lastname: Wooderchak-Donahue
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
authors.forename: Chad
authors.initials: C
authors.lastname: VanSant-Webb
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tvrdik
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
authors.forename: Parker
authors.initials: P
authors.lastname: Plant
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
authors.forename: Tracey
authors.initials: T
authors.lastname: Lewis
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stocks
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Raney
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Meyers
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah.
authors.forename: Alizabeth
authors.initials: A
authors.lastname: Berg
authors.affiliation: Department of Medical Genetics, Kaiser Permanente, Portland, Oregon.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Rope
authors.affiliation: Department of Pediatrics, Division of Cardiology, University of Utah, Salt Lake City, Utah.
authors.forename: Anji T
authors.initials: AT
authors.lastname: Yetman
authors.affiliation: Department of Pediatrics, Division of Cardiology, University of Utah, Salt Lake City, Utah.|Clinical Genetics Institute, Intermountain Healthcare, Salt Lake City, Utah.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bleyl
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mesley
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah.
authors.forename: David A
authors.initials: DA
authors.lastname: Bull
authors.affiliation: Department of Pediatrics and Internal Medicine, Cardiology Division, Arkansas Children's Hospital, Little Rock, Arkansas.
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Collins
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Mayra Martinez
authors.initials: MM
authors.lastname: Ojeda
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Amy
authors.initials: A
authors.lastname: Roberts
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Ronald
authors.initials: R
authors.lastname: Lacro
authors.affiliation: Division of Genetics, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Audrey
authors.initials: A
authors.lastname: Woerner
authors.affiliation: Division of Genetics, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Joan
authors.initials: J
authors.lastname: Stoler
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.|Department of Pathology, University of Utah, Salt Lake City, Utah.
authors.forename: Pinar
authors.initials: P
authors.lastname: Bayrak-Toydemir
mesh_terms: D001018:Aortic Diseases / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: Marfan syndrome; aorta; aortic aneurysm; diagnosis; dilation; dissection; ductus arteriosus