Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches.
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ABSTRACT:
SUBMITTER: Arslan-Kirchner M
PROVIDER: S-EPMC4795237 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
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Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches.
Arslan-Kirchner Mine M Arbustini Eloisa E Boileau Catherine C Charron Philippe P Child Anne H AH Collod-Beroud Gwenaelle G De Backer Julie J De Paepe Anne A Dierking Anna A Faivre Laurence L Hoffjan Sabine S Jondeau Guillaume G Keyser Britta B Loeys Bart B Mayer Karin K Robinson Peter N PN Schmidtke Jörg J
European journal of human genetics : EJHG 20151028 1
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Project description:1. NAME OF THE DISEASE (SYNONYMS): Primary congenital glaucoma (PCG). Glaucoma, congenital (GLC). 2. OMIM# OF THE DISEASE: 231300- GLC3A. 600975- GLC3B. 613085- GLC3C. 613086- GLC3D. 617272- GLC3E. 3. NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME SEGMENTS: CYP1B1. LTBP2. MYOC. FOXC1. TEK. 4. OMIM# OF THE GENE(S): CYP1B1 MIM# 601771. LTBP2 MIM# 602091. MYOC MIM# 601652. FOXC1 MIM# 601090. TEK MIM# 600221. Review of the analytical and clinical validity, as well as of the clinical utility of DNA-based testing for variants in the CYP1B1, LTBP2 and MYOC gene(s) in ⊠ diagnostic, ⊠ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.
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Project description:AimsThoracic aortic aneurysm/dissection (TAAD) is a life-threatening disease with diverse clinical manifestations. Although the association between methamphetamine (METH) and TAAD is frequently observed, the causal relationship between METH abuse and aortic aneurysm/dissection has not been established. This study was designed to determine if METH causes aortic aneurysm/dissection and delineate the underlying mechanism.Methods and resultsA new TAAD model was developed by exposing METH to SD rats pre-treated with lysyl oxidase inhibitor β-aminopropionitrile (BAPN). Combination of METH and BAPN caused thoracic aortic aneurysm/dissection in 60% of rats. BAPN+METH significantly increased the expression and activities of both matrix metalloproteinase MMP2 and MMP9, consistent with the severe elastin breakage and dissection. Mechanistically, METH increased CCAAT-enhancer binding protein β (C/EBPβ) expression by enhancing mothers against decapentaplegic homolog 3 (Smad3) and extracellular regulated protein kinase (ERK1/2) signaling. METH also promoted C/EBPβ binding to MMP2 and MMP9 promoters. Blocking C/EBPβ significantly attenuated METH+BAPN-induced TAAD and MMP2/MMP9 expression. Moreover, BAPN+METH promoted aortic medial smooth muscle cell (SMC) apoptosis through C/EBPβ-mediated IGFBP5/p53/PUMA signaling pathways. More importantly, the expression of C/EBPβ, MMP2/MMP9, and apoptosis-promoting proteins was increased in the aorta of human patients with thoracic aortic dissection, suggesting that the mechanisms identified in animal study could be relevant to human disease.ConclusionsOur study demonstrated that METH exposure has a casual effect on TAAD. C/EBPβ mediates METH-introduced TAAD formation by causing elastin breakage, medial cell loss and degeneration. Therefore, C/EBPβ may be a potential factor for TAAD clinical diagnosis or treatment.
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Project description:Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair.
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Project description:BackgroundThoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.ObjectivesThe purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework.MethodsWe applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel.ResultsGenes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD.ConclusionsThe ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.
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Project description:ObjectiveThoracic aortic aneurysm and dissection (TAAD) is a cardiovascular disease with a high mortality rate. Aging is an important risk factor for TAAD. This study explored the relationship between aging and TAAD and investigated the underlying mechanisms, which may contribute to the diagnosis and treatment of TAAD.MethodsHuman aging genes were obtained from the Aging Atlas official website. Various datasets were downloaded from the GEO database:the human TAAD dataset GSE52093 were used for screening differentially expressed genes (DEGs); GSE137869, GSE102397 and GSE153434 were used as validation sets, and GSE9106 was used for diagnostic prediction of receiver operating characteristic (ROC) curves. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction (PPI) network analysis were used to screen differentially co-expressed genes from human aging genes and TAAD. Using five methods of the cytoHubba plugin in Cytoscape software (Degree, Closeness, EPC, MNC, Radiality), hub genes were identified from the differentially co-expressed genes. Single-cell RNA sequencing was used to verify the expression levels of hubgenes in different cell types of aortic tissue. ROC curves were used to further screen for diagnostic genes.ResultsA total of 70 differentially co-expressed genes were screened from human aging genes and DEGs in human TAAD dataset GSE52093. GO enrichment analysis revealed that the DEGs played a major role in regulating DNA metabolism and damaged DNA binding. KEGG enrichment analysis revealed enrichment in the longevity regulating pathway, cellular senescence, and HIF-1 signaling pathway. GSEA indicated that the DEGs were concentrated in the cell cycle and aging-related p53 signaling pathway. The five identified hubgenes were MYC, IL6, HIF1A, ESR1, and PTGS2. Single-cell sequencing of the aging rat aorta showed that hubgenes were expressed differently in different types of cells in aortic tissue. Among these five hubgenes, HIF1A and PTGS2 were validated in the aging dataset GSE102397; MYC, HIF1A and ESR1 were validated in the TAAD dataset GSE153434. The combined area under the diagnostic ROC curve (AUC) values for the five hub genes were >0.7 in the testing and training sets of the dataset GSE9106. The combined AUC values of MYC and ESR1 were equal to the combin ed AUC values of the five hub genes.ConclusionThe HIF-1 signaling pathway may play an important role in TAAD and aging. MYC and ESR1 may have diagnostic value for aging-related TAAD.
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Project description:Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca2+ concentration-multiple calcium channel expression and ADP-ribose synthesis-were attenuated in Myh11ΔK/ΔK aortas. We suggest that the impairment of the Ca2+ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.
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Project description:Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening pathology and remains challenging worldwide. Up to 40% of TAAD are hereditary with complex heterogeneous genetic backgrounds. Recently, next-generation sequencing (NGS) has been successfully applied to identify genetic variants in an efficient and cost-effective manner. In our study, NGS coupled with DNA target-capture array was used to screen 11 known causative genes of TAAD in 70 patients from Southern China. All the identified variants were confirmed by Sanger sequencing. We identified forty variants in 36 patients (51.4%), including three known pathogenic (7.5%), 10 likely pathogenic variants (25%, 9 in FBN1, 1 in ACTA2), and 27 variants with uncertain significance (VUS) (67.5%). Among the 27 VUS, 14 (51.9%) were in the FBN1 gene, 3 in Col5A2, 2 in ACTA2, 2 in MYH11, 2 in MYLK, 2 in SLC2A10, 1 in MSTN and 1 in SMAD3 respectively. Based on the segregation data and independent reports, five known likely pathogenic variants and four VUS were upgraded to pathogenic variant and likely pathogenic variant respectively. Our data indicate that NGS is a highly efficient genetic method for identification of pathogenic variants in TAAD patients.
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