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

Meester, J. A.; Vandeweyer, G.; Pintelon, I.; Lammens, M.; Van Hoorick, L.; De Belder, S.; Waitzman, K.; Young, L.; Markham, L. W.; Vogt, J.; Richer, J.; Beauchesne, L. M.; Unger, S.; Superti-Furga, A.; Prsa, M.; Dhillon, R.; Reyniers, E.; Dietz, H. C.; Wuyts, W.; Mortier, G.; Verstraeten, A.; Van Laer, L.; Loeys, B. L.

Genet Med. 2016 Sep 16


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-beta 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-beta signaling.Genet Med advance online publication 15 September 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.126.

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