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• W3023483631 abstract "Pseudoxanthoma elasticum (PXE), an autosomal recessive ectopic mineralization disorder caused by mutations in the ABCC6 and ENPP1 gene is characterized by skin, ocular and cardiovascular (CV) symptoms. However, an important variability in clinical severity is seen in patients, which does not correlate with their genotype. This suggests that other factors such as modifier genes and epigenetic mechanisms may influence phenotypic heterogeneity. The limited data on modifier genes in PXE results mainly from the use of a candidate gene approach based on current knowledge on the mechanisms underlying PXE; to date only VEGFA (encoding vascular endothelial growth factor) has been confirmed as a modifier gene for the PXE retinopathy. The pathophysiology of PXE is not well understood, hampering the selection of putative modifier candidates. Further it is probable that in an individual patient multiple modifier genes play a (synergistic) role, favoring a technology capable of analyzing multiple genes in a single reaction for their identification. Given that PXE is a rare disease, it is also difficult to generate cohorts large enough for proper statistical analysis. To tackle all of these hurdles, we introduced Whole Exome Sequencing (WES) as a new technique to identify potential modifier genes, by comparing patients with extreme phenotypes. A similar approach was already proven successful in identifying modifiers in cystic fibrosis. In this pilot study, WES was performed in 13 molecularly and histologically confirmed PXE patients with an extreme (mild or severe) CV phenotype (based on clinical presentation and vascular calcium (Agatston) scoring using whole body CT). We performed targeted analysis of variants unique for the severely affected cohort. Out of 1372 variants in the original dataset, we withheld 108 variants after initial selection of genes involved in mineralization, occlusive and atherosclerotic coronary and peripheral vessel disease, vitamin K and magnesium metabolism. The number of variants was narrowed down using in silico prediction tools (SIFT, Polyphen, PhyloP, Mutation taster and LRT) and a comprehensive literature study. As a result, 9 variants were withheld, which were all validated using Sanger Sequencing and screened in a second, independent cohort of 50 PXE patients with mild or severe CV disease based on the criteria mentioned above. Genotype- and allele frequency analysis and multiple logistic regression confirmed significant association of 3 SNPs with severe CV disease: rs2228570 (VDR gene), rs13006529 (CASP10 gene) and rs1042714 (ADRB2 gene). All SNPs were previously linked to CV disease; functional data mining also yielded links to the PXE pathophysiology. Particularly for the VDR variant, reported to cause increased transcriptional activity of VDR, upregulation of several transcriptional VDR targets in PXE was found.In conclusion, WES enables us to characterize candidate modifier genes by applying a targeted analysis approach in patients with extreme phenotypes, making it feasible to obtain significant results despite a relatively small sample size. After an essential confirmation in an independent cohort, the first results of this study point towards a role of VDR, CASP10 and ADRB2 in the cardiovascular presentation and pathophysiology of PXE, providing valuable assets for the management of PXE families." @default.
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• W3023483631 date "2015-01-01" @default.
• W3023483631 modified "2023-09-27" @default.
• W3023483631 title "Whole exome sequencing as a novel tool for the detection of modifier genes in pseudoxanthoma elasticum" @default.
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