Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections

Josephina A.N. Meester, Geert Vandeweyer, Isabel Pintelon, Martin Lammens, Lana Van Hoorick, Simon De Belder, Kathryn Waitzman, Luciana Young, Larry W. Markham, Julie Vogt, Julie Richer, Luc M. Beauchesne, Sheila Unger, Andrea Superti-Furga, Milan Prsa, Rami Dhillon, Edwin Reyniers, Harry C. DIetz, Wim Wuyts, Geert MortierAline Verstraeten, Lut Van Laer, Bart L. Loeys

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)386-395
Number of pages10
JournalGenetics in Medicine
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2017

Keywords

  • BGN
  • Loeys-Dietz syndrome
  • Marfan syndrome
  • biglycan
  • thoracic aortic aneurysm

ASJC Scopus subject areas

  • Genetics(clinical)

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