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Efficiency of exome sequencing for the molecular diagnosis and modifier gene identification in pseudoxanthoma elasticum

Eva De Vilder (UGent) , Mohammad Jakir Hosen (UGent) and Olivier Vanakker (UGent)
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Organization
Abstract
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.
Keywords
modifier gene, whole exome sequencing, Pseudoxanthoma elasticum, peripheral artery disease, ABCC6, cardiovascular disease, VDR

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MLA
De Vilder, Eva, Mohammad Jakir Hosen, and Olivier Vanakker. “Efficiency of Exome Sequencing for the Molecular Diagnosis and Modifier Gene Identification in Pseudoxanthoma Elasticum.” Wetenschapsdag, Samenvattingen. Universiteit Gent. Faculteit Geneeskunde en Gezondheidswetenschappen, 2015. Print.
APA
De Vilder, E., Hosen, M. J., & Vanakker, O. (2015). Efficiency of exome sequencing for the molecular diagnosis and modifier gene identification in pseudoxanthoma elasticum. Wetenschapsdag, Samenvattingen. Presented at the Wetenschapsdag 2015, Universiteit Gent. Faculteit Geneeskunde en Gezondheidswetenschappen.
Chicago author-date
De Vilder, Eva, Mohammad Jakir Hosen, and Olivier Vanakker. 2015. “Efficiency of Exome Sequencing for the Molecular Diagnosis and Modifier Gene Identification in Pseudoxanthoma Elasticum.” In Wetenschapsdag, Samenvattingen. Universiteit Gent. Faculteit Geneeskunde en Gezondheidswetenschappen.
Chicago author-date (all authors)
De Vilder, Eva, Mohammad Jakir Hosen, and Olivier Vanakker. 2015. “Efficiency of Exome Sequencing for the Molecular Diagnosis and Modifier Gene Identification in Pseudoxanthoma Elasticum.” In Wetenschapsdag, Samenvattingen. Universiteit Gent. Faculteit Geneeskunde en Gezondheidswetenschappen.
Vancouver
1.
De Vilder E, Hosen MJ, Vanakker O. Efficiency of exome sequencing for the molecular diagnosis and modifier gene identification in pseudoxanthoma elasticum. Wetenschapsdag, Samenvattingen. Universiteit Gent. Faculteit Geneeskunde en Gezondheidswetenschappen; 2015.
IEEE
[1]
E. De Vilder, M. J. Hosen, and O. Vanakker, “Efficiency of exome sequencing for the molecular diagnosis and modifier gene identification in pseudoxanthoma elasticum,” in Wetenschapsdag, Samenvattingen, Gent, 2015.
@inproceedings{7050992,
  abstract     = {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.},
  author       = {De Vilder, Eva and Hosen, Mohammad Jakir and Vanakker, Olivier},
  booktitle    = {Wetenschapsdag, Samenvattingen},
  keywords     = {modifier gene,whole exome sequencing,Pseudoxanthoma elasticum,peripheral artery disease,ABCC6,cardiovascular disease,VDR},
  language     = {eng},
  location     = {Gent},
  publisher    = {Universiteit Gent. Faculteit Geneeskunde en Gezondheidswetenschappen},
  title        = {Efficiency of exome sequencing for the molecular diagnosis and modifier gene identification in pseudoxanthoma elasticum},
  year         = {2015},
}