Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of lynch syndrome patients
✍ Scribed by Heleen M. van der Klift; Carli M.J. Tops; Elsa C. Bik; Merel W. Boogaard; Anne-Marijke Borgstein; Kerstin B.M. Hansson; Margreet G.E.M. Ausems; Encarna Gomez Garcia; Andrew Green; Frederik J. Hes; Louise Izatt; Liselotte P. van Hest; Angel M. Alonso; Annette H.J.T. Vriends; Anja Wagner; Wendy A.G. van Zelst-Stams; Hans F.A. Vasen; Hans Morreau; Peter Devilee; Juul T. Wijnen
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 592 KB
- Volume
- 31
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We investigated the frequency of such events with a nonspecific polymerase chain reaction (PCR) strategy, coamplifying both PMS2 and PMS2CL sequences. This allowed us to score ratios between gene and pseudogene-specific nucleotides at 29 PSV sites from exon 11 to the end of the gene. We found sequence transfer at all investigated PSVs from intron 12 to the 3 0 end of the gene in 4 to 52% of DNA samples. Overall, sequence exchange between PMS2 and PMS2CL was observed in 69% (83/ 120) of individuals. We demonstrate that mutation scanning with PMS2-specific PCR primers and MLPA probes, designed on PSVs, in the 3 0 duplicated region is unreliable, and present an RNA-based mutation detection strategy to improve reliability. Using this strategy, we found 19 different putative pathogenic PMS2 mutations. Four of these (21%) are lying in the region with frequent sequence transfer and are missed or called incorrectly as homozygous with several PSV-based mutation detection methods.