A Comprehensive Strategy for Accurate Mutation Detection of the Highly Homologous PMS2

The Journal of Molecular Diagnostics : JMD
Jianli LiLee-Jun C Wong

Abstract

Germline mutations in the DNA mismatch repair gene PMS2 underlie the cancer susceptibility syndrome, Lynch syndrome. However, accurate molecular testing of PMS2 is complicated by a large number of highly homologous sequences. To establish a comprehensive approach for mutation detection of PMS2, we have designed a strategy combining targeted capture next-generation sequencing (NGS), multiplex ligation-dependent probe amplification, and long-range PCR followed by NGS to simultaneously detect point mutations and copy number changes of PMS2. Exonic deletions (E2 to E9, E5 to E9, E8, E10, E14, and E1 to E15), duplications (E11 to E12), and a nonsense mutation, p.S22*, were identified. Traditional multiplex ligation-dependent probe amplification and Sanger sequencing approaches cannot differentiate the origin of the exonic deletions in the 3' region when PMS2 and PMS2CL share identical sequences as a result of gene conversion. Our approach allows unambiguous identification of mutations in the active gene with a straightforward long-range-PCR/NGS method. Breakpoint analysis of multiple samples revealed that recurrent exon 14 deletions are mediated by homologous Alu sequences. Our comprehensive approach provides a reliable tool for acc...Continue Reading

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Jul 9, 2016·Expert Review of Molecular Diagnostics·Ahmad N Abou TayounNancy B Spinner
Mar 2, 2017·The American Journal of Surgical Pathology·Felipe C C SilvaDirce M Carraro
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Jun 22, 2021·Current Opinion in Immunology·Neftali J RamirezBodo Grimbacher
Oct 10, 2021·Pediatric Transplantation·Amber GibsonSajad Khazal

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