Improved multiplex ligation-dependent probe amplification analysis identifies a deleterious PMS2 allele generated by recombination with crossover between PMS2 and PMS2CL.

Genes, Chromosomes & Cancer
A WernstedtKatharina Wimmer

Abstract

Heterozygous PMS2 germline mutations are associated with Lynch syndrome. Up to one third of these mutations are genomic deletions. Their detection is complicated by a pseudogene (PMS2CL), which--owing to extensive interparalog sequence exchange--closely resembles PMS2 downstream of exon 12. A recently redesigned multiplex ligation-dependent probe amplification (MLPA) assay identifies PMS2 copy number alterations with improved reliability when used with reference DNAs containing equal numbers of PMS2- and PMS2CL-specific sequences. We selected eight such reference samples--all publicly available--and used them with this assay to study 13 patients with PMS2-defective colorectal tumors. Three presented deleterious alterations: an Alu-mediated exon deletion; a 125-kb deletion encompassing PMS2 and four additional genes (two with tumor-suppressing functions); and a novel deleterious hybrid PMS2 allele produced by recombination with crossover between PMS2 and PMS2CL, with the breakpoint in intron 10 (the most 5' breakpoint of its kind reported thus far). We discuss mechanisms that might generate this allele in different chromosomal configurations (and their diagnostic implications) and describe an allele-specific PCR assay that facil...Continue Reading

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Citations

Apr 17, 2014·Journal of Medical Genetics·Katharina WimmerUNKNOWN EU-Consortium Care for CMMRD (C4CMMRD)
Jul 11, 2013·Clinical Genetics·A J Brea-FernándezC Ruiz-Ponte
Jun 23, 2016·European Journal of Human Genetics : EJHG·Julia VogtKatharina Wimmer
Nov 7, 2013·Clinical Chemistry·Laura J TafeGregory J Tsongalis
Oct 17, 2019·European Journal of Human Genetics : EJHG·Anne M L JansenHans Morreau

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Datasets Mentioned

BETA
GM10842
NA07019
GM07019
NA12853
GM12853
GM17002
NA17005
GM17005
GM17008
GM17009

Methods Mentioned

BETA
PCR
Assay
two hybrid
electrophoresis
ubiquitination

Software Mentioned

R
Progenetix

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