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Efficiency of exome sequencing for the molecular diagnosis of Pseudoxanthoma Elasticum

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Abstract
The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, next-generation sequencing (NGS) allows to perform mutation screening of several genes in a single reaction. We explored whole-exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1, and vitamin K epoxide reductase complex, subunit 1 (VKORC1) in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exonnes with insufficient reads (<= 20 depth) for the four genes and patients with single mutations were further evaluated by Sanger sequencing (SS), but no additional mutations were found. The potential of WES compared with targeted NGS is the ease to examine target genes and the opportunity to search for novel genes when targeted analysis is negative. Together with low cost, rapid and less laborious workflow, we conclude that WES complemented with SS can provide a tiered approach to molecular diagnostics of PXE.
Keywords
COMPOUND HETEROZYGOSITY, ABCC6 GENE, CALCIFICATION DISORDERS, MUTATION DETECTION, BETA-THALASSEMIA, CUTIS LAXA, PHENOTYPE, IDENTIFICATION, SPECTRUM, PXE

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Citation

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MLA
Hosen, Mohammad Jakir, Filip Van Nieuwerburgh, Wouter Steyaert, et al. “Efficiency of Exome Sequencing for the Molecular Diagnosis of Pseudoxanthoma Elasticum.” JOURNAL OF INVESTIGATIVE DERMATOLOGY 135.4 (2015): 992–998. Print.
APA
Hosen, M. J., Van Nieuwerburgh, F., Steyaert, W., Deforce, D., Martin, L., Leftheriotis, G., De Paepe, A., et al. (2015). Efficiency of exome sequencing for the molecular diagnosis of Pseudoxanthoma Elasticum. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 135(4), 992–998.
Chicago author-date
Hosen, Mohammad Jakir, Filip Van Nieuwerburgh, Wouter Steyaert, Dieter Deforce, Ludovic Martin, Georges Leftheriotis, Anne De Paepe, Paul Coucke, and Olivier Vanakker. 2015. “Efficiency of Exome Sequencing for the Molecular Diagnosis of Pseudoxanthoma Elasticum.” Journal of Investigative Dermatology 135 (4): 992–998.
Chicago author-date (all authors)
Hosen, Mohammad Jakir, Filip Van Nieuwerburgh, Wouter Steyaert, Dieter Deforce, Ludovic Martin, Georges Leftheriotis, Anne De Paepe, Paul Coucke, and Olivier Vanakker. 2015. “Efficiency of Exome Sequencing for the Molecular Diagnosis of Pseudoxanthoma Elasticum.” Journal of Investigative Dermatology 135 (4): 992–998.
Vancouver
1.
Hosen MJ, Van Nieuwerburgh F, Steyaert W, Deforce D, Martin L, Leftheriotis G, et al. Efficiency of exome sequencing for the molecular diagnosis of Pseudoxanthoma Elasticum. JOURNAL OF INVESTIGATIVE DERMATOLOGY. 2015;135(4):992–8.
IEEE
[1]
M. J. Hosen et al., “Efficiency of exome sequencing for the molecular diagnosis of Pseudoxanthoma Elasticum,” JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 135, no. 4, pp. 992–998, 2015.
@article{5755757,
  abstract     = {The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, next-generation sequencing (NGS) allows to perform mutation screening of several genes in a single reaction. We explored whole-exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1, and vitamin K epoxide reductase complex, subunit 1 (VKORC1) in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exonnes with insufficient reads (<= 20 depth) for the four genes and patients with single mutations were further evaluated by Sanger sequencing (SS), but no additional mutations were found. The potential of WES compared with targeted NGS is the ease to examine target genes and the opportunity to search for novel genes when targeted analysis is negative. Together with low cost, rapid and less laborious workflow, we conclude that WES complemented with SS can provide a tiered approach to molecular diagnostics of PXE.},
  author       = {Hosen, Mohammad Jakir and Van Nieuwerburgh, Filip and Steyaert, Wouter and Deforce, Dieter and Martin, Ludovic and Leftheriotis, Georges and De Paepe, Anne and Coucke, Paul and Vanakker, Olivier},
  issn         = {1081-5589},
  journal      = {JOURNAL OF INVESTIGATIVE DERMATOLOGY},
  keywords     = {COMPOUND HETEROZYGOSITY,ABCC6 GENE,CALCIFICATION DISORDERS,MUTATION DETECTION,BETA-THALASSEMIA,CUTIS LAXA,PHENOTYPE,IDENTIFICATION,SPECTRUM,PXE},
  language     = {eng},
  number       = {4},
  pages        = {992--998},
  title        = {Efficiency of exome sequencing for the molecular diagnosis of Pseudoxanthoma Elasticum},
  url          = {http://dx.doi.org/10.1038/jid.2014.421},
  volume       = {135},
  year         = {2015},
}

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