title: Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.
abstract: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families.
  
  
  
  We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed.
  
  
  
  We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture.
  
  
  
  In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395.
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Josephina A N
authors.initials: JA
authors.lastname: Meester
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Vandeweyer
authors.affiliation: Department of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pintelon
authors.affiliation: Department of Pathology, University Hospital Antwerp, University of Antwerp, Antwerp, Belgium.
authors.forename: Martin
authors.identifier: 0000-0002-3881-6692
authors.initials: M
authors.lastname: Lammens
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Lana
authors.identifier: 0000-0002-6702-3122
authors.initials: L
authors.lastname: Van Hoorick
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Simon
authors.identifier: 0000-0002-3220-3991
authors.initials: S
authors.lastname: De Belder
authors.affiliation: Department of Pediatric Cardiology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Waitzman
authors.affiliation: Department of Pediatric Cardiology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
authors.forename: Luciana
authors.initials: L
authors.lastname: Young
authors.affiliation: Divisions of Pediatric and Adult Cardiology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Larry W
authors.identifier: 0000-0001-5968-939X
authors.initials: LW
authors.lastname: Markham
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Vogt
authors.affiliation: Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Richer
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Luc M
authors.identifier: 0000-0003-4288-1945
authors.initials: LM
authors.lastname: Beauchesne
authors.affiliation: Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.affiliation: Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Milan
authors.identifier: 0000-0002-9483-7957
authors.initials: M
authors.lastname: Prsa
authors.affiliation: The Heart Unit, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Rami
authors.initials: R
authors.lastname: Dhillon
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Edwin
authors.initials: E
authors.lastname: Reyniers
authors.affiliation: Howard Hughes Medical Institute, Baltimore, Maryland, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Harry C
authors.identifier: 0000-0002-6856-0165
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Wuyts
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Aline
authors.initials: A
authors.lastname: Verstraeten
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Lut
authors.identifier: 0000-0003-1394-9867
authors.initials: L
authors.lastname: Van Laer
authors.affiliation: Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
mesh_terms: D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000378:metabolism; D058578:Biglycan / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D050172:Genes, X-Linked; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C546884:BGN protein, human; D058578:Biglycan; D016212:Transforming Growth Factor beta