title: Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.
abstract: BACKGROUND
  Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner.
  
  
  OBJECTIVE
  To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants.
  
  
  RESULTS
  A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers.
  
  
  CONCLUSIONS
  SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Regalado
authors.forename: Dong-Chuan
authors.initials: DC
authors.lastname: Guo
authors.forename: Carlos
authors.initials: C
authors.lastname: Villamizar
authors.forename: Nili
authors.initials: N
authors.lastname: Avidan
authors.forename: Dawna
authors.initials: D
authors.lastname: Gilchrist
authors.forename: Barbara
authors.initials: B
authors.lastname: McGillivray
authors.forename: Lorne
authors.initials: L
authors.lastname: Clarke
authors.forename: Francois
authors.initials: F
authors.lastname: Bernier
authors.forename: Regie L
authors.initials: RL
authors.lastname: Santos-Cortez
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D000784:Aortic Dissection / Q000175:diagnosis / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D002532:Intracranial Aneurysm / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D051900:Smad3 Protein / Q000235:genetics*
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein