Shana Verschuere
Paul J. Coucke
Olivier M. Vanakker
a Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium;
b Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
Funds: This research was supported by a Methusalem grant (BOF08/01M01108) from Ghent University. The computational resources (Stevin Supercomputer Infrastructure) and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by Ghent University, FWO and the Flemish Governmentddepartment EWI.
Received Date: 2020-09-18
Accepted Date:2021-02-09
Rev Recd Date:2021-02-03
Publish Date:2021-04-20
Abstract
Abstract
Pseudogenes are frequently encountered noncoding sequences with a high sequence similarity to their protein-coding paralogue. For this reason, their presence is often considered troublesome in molecular diagnostics. In pseudoxanthoma elasticum (PXE), a disease predominantly caused by mutations in ATPbinding cassette family C member 6 (ABCC6), the presence of two pseudogenes complicates the analysis of sequence data. With whole-exome sequencing (WES) becoming the standard of care in molecular diagnostics, we wanted to evaluate whether this technique is as reliable as gene-specific targeted enrichment analysis for the analysis of ABCC6. We established a PCR-based targeted enrichment and next-generation sequencing testing approach and demonstrated that the ABCC6-specific enrichment combined with the applied mapping algorithm overcomes the complication of ABCC6 pseudogene aspecificities, contrary to WES. We propose a time- and cost-efficient diagnostic strategy for comprehensive and accurate molecular genetic testing of PXE, which is highly automatable.Keywords: Pseudoxanthoma elasticum,
ABCC6,
Pseudogenes,
Next-generation sequencing,
Whole-exome sequencing,
Targeted enrichment
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