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Genet Med. 2017 Apr;19(4):386-395. doi: 10.1038/gim.2016.126. Epub 2016 Sep 15.

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

Author information

1
Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
2
Department of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
3
Department of Pathology, University Hospital Antwerp, University of Antwerp, Antwerp, Belgium.
4
Department of Pediatric Cardiology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
5
Divisions of Pediatric and Adult Cardiology, Vanderbilt University, Nashville, Tennessee, USA.
6
West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
7
Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
8
Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
9
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
10
Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
11
The Heart Unit, Birmingham Children's Hospital, Birmingham, UK.
12
Howard Hughes Medical Institute, Baltimore, Maryland, USA.
13
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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.Genet Med 19 4, 386-395.

PMID:
27632686
PMCID:
PMC5207316
DOI:
10.1038/gim.2016.126
[Indexed for MEDLINE]
Free PMC Article

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