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Efficiency of exome sequencing for the molecular diagnosis and modifier gene identification in pseudoxanthoma elasticum
Book Contribution - Book Abstract Conference Contribution
The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive ectopic mineralization disorder, has become more complex as mutations in multiple genes - ABCC6, ENPP1 and GGCX - can cause similar phenotypes. Further, PXE shows important clinical variability, with growing importance of modifier genes. Thus, often multiple genes need to be screened in a patient. Next Generation Sequencing, including whole exome sequencing (WES), allows to analyse several genes in 1 reaction. First, we explored WES as a diagnostic tool to identify mutations in PXE-related genes in 16 PXE patients, and show it to be a cost-effective method with high mutation detection rate (94%). Second, WES is used for the identification of modifier genes, by comparing patients with extreme phenotypes. A pilot study in 13 PXE patients with an extreme (mild or severe) cardiovascular (CV) phenotype (based on vascular calcium scoring, clinical presentation and evolution), led us to withhold 9 variants which were subsequently validated using Sanger Sequencing and screened in an independent cohort of 50 PXE patients. Genotype- and allele frequency analysis and multiple logistic regression led us to retain 3 SNPs associated with severe CV disease: rs2228570 (VDR gene), rs13006529 (CASP10 gene) and rs1042714 (ADRB2 gene). All were previously linked to CV disease and functional data mining yielded potential (in)direct links to the PXE pathophysiology in 2 variants, which are further investigated. In conclusion, WES provides an efficient tool for molecular diagnosis in polygenic diseases and, even in orphan disorders, is a promising tool for modifier identification using an extreme phenotype approach. It thus contributes to the efficiency of diagnostics and management in orphan disease patients.
Book: Wetenschapsdag, Samenvattingen
Number of pages: 1