Communicated by Finlay Macrae
Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of lynch syndrome patients†
Article first published online: 25 FEB 2010
© 2010 Wiley-Liss, Inc.
Volume 31, Issue 5, pages 578–587, May 2010
How to Cite
van der Klift, H. M., Tops, C. M.J., Bik, E. C., Boogaard, M. W., Borgstein, A.-M., Hansson, K. B.M., Ausems, M. G.E.M., Garcia, E. G., Green, A., Hes, F. J., Izatt, L., van Hest, L. P., Alonso, A. M., Vriends, A. H.J.T., Wagner, A., van Zelst-Stams, W. A.G., Vasen, H. F.A., Morreau, H., Devilee, P. and Wijnen, J. T. (2010), Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of lynch syndrome patients. Hum. Mutat., 31: 578–587. doi: 10.1002/humu.21229
- Issue published online: 29 APR 2010
- Article first published online: 25 FEB 2010
- Accepted manuscript online: 25 FEB 2010 12:00AM EST
- Manuscript Accepted: 12 FEB 2010
- Manuscript Received: 7 SEP 2009
- Lynch syndrome;
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′ 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′ 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. Hum Mutat 31:578–587, 2010. © 2010 Wiley-Liss, Inc.