Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.
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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.
SUBMITTER: Meester JA
PROVIDER: S-EPMC5207316 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThoracic aortic aneurysms and dissections (TAAD) is a critical condition that often goes undiagnosed with fatal consequences. While majority of the cases are sporadic, more than 20% are inherited as a single gene disorder. The most common familial TAA is Marfan syndrome (MFS), which is primarily caused by mutations in fibrillin-1 (FBN1) gene. Patients with FBN1 mutations are at higher risk for dissection compared to other patients with similar size aneurysms.MethodsFifteen family members were genotyped using Affymetrix-10K genechips. A genome-wide association study was carried out using an autosomal dominant model of inheritance with incomplete penetrance. Mutation screening of all exons and exon-intron boundaries of FBN1 gene which reside near the peak Lod score was carried out by direct sequencing.ResultsThe index case presented with agonizing substernal pain and was found to have TAAD by transthoracic echocardiogram. The family history was significant for 3 first degree relatives with TAA. Nine additional family members were diagnosed with TAA by echocardiography examinations. The affected individuals had no syndromic features. A genome-wide analysis of linkage mapped the disease gene to a single locus on chromosome 15q21 with a peak Lod score of 3.6 at fibrillin-1 (FBN1) gene locus (odds ratio > 4000:1 in favour of linkage), strongly suggesting that FBN1 is the causative gene. No mutation was identified within the exons and exon-intron boundaries of FBN1 gene that segregated with the disease. Haplotype analysis identified additional mutation carriers who had previously unknown status due to borderline dilation of the ascending aorta.ConclusionsA familial non-syndromic TAAD is strongly associated with the FBN1 gene locus and has a malignant disease course often seen in MFS patients. This finding indicates the importance of obtaining detailed family history and echocardiographic screening of extended relatives of patients with non-syndromic TAAD to improve the outcome. In addition, association of non-syndromic TAAD with the Marfan disease gene locus poses the question whether secondary prevention strategies employed for Marfan syndrome patients should be applied to all patients with familial TAAD.
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Project description:BackgroundThoracic aortic aneurysm and dissection (TAAD) is a hidden-onset but life-threatening disorder with high clinical variability and genetic heterogeneity. In recent years, an increasing number of genes have been identified to be related to TAAD. However, some genes remain uncertain because of limited case reports and/or functional studies. LTBP3 was such an ambiguous gene that was previously known for dental and skeletal dysplasia and then noted to be associated with TAAD. More research on individuals or families harboring variants in this gene would be helpful to obtain full knowledge of the disease and clarify its association with TAAD.MethodsA total of 266 TAAD probands with no causative mutations in known genes had been performed wholeexome sequencing (WES) to identify potentially pathogenic variants. In this study, rare LTBP3 variants were the focus of analysis.ResultsTwo compound heterozygous mutations, c.625dup (p.Leu209fs) and c.1965del (p.Arg656fs), in LTBP3 were identified in a TAAD patient along with short stature and dental problems, which was the first TAAD case with biallelic LTBP3 null mutations in an Asian population. Additionally, several rare heterozygous LTBP3 variants were also detected in other sporadic TAAD patients.ConclusionThe identification of LTBP3 mutations in TAAD patients in our study provided more clinical evidence to support its association with TAAD, which broadens the gene spectrum of LTBP3. LTBP3 should be considered to be incorporated into the routine genetic analysis of heritable aortopathy, which might help to fully understand its phenotypic spectrum and improve the diagnostic rate of TAAD.
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