Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients
Article first published online: 10 NOV 2005
Copyright © 2005 Wiley-Liss, Inc.
Genes, Chromosomes and Cancer
Volume 45, Issue 3, pages 265–276, March 2006
How to Cite
Wimmer, K., Yao, S., Claes, K., Kehrer-Sawatzki, H., Tinschert, S., De Raedt, T., Legius, E., Callens, T., Beiglböck, H., Maertens, O. and Messiaen, L. (2006), Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosom. Cancer, 45: 265–276. doi: 10.1002/gcc.20289
- Issue published online: 27 DEC 2005
- Article first published online: 10 NOV 2005
- Manuscript Accepted: 5 OCT 2005
- Manuscript Received: 5 AUG 2005
Neurofibromatosis type 1 (NF1), the most common tumor-predisposing disorder in humans, is caused by defects in the NF1 tumor-suppressor gene. Comprehensive mutation analysis applying RNA-based techniques complemented with FISH analysis achieves mutation detection rates of ∼95% in NF1 patients. The majority of mutations are minor lesions, and ∼5% are total gene deletions. We found 13 single- and/or multiexon deletions/duplications out of 1,050 detected mutations using our RNA-based approach in a cohort of 1,100 NF1 patients and confirmed these changes using multiplex ligation-dependent probe amplification (MLPA). With MLPA, we found another 12 novel multiexon deletion/duplications in 55 NF1 patients for whom analysis with multiple assays had not revealed a NF1 mutation, including 50 previously analyzed comprehensively. The extent of the 22 deletions and 3 duplications varied greatly, and there was no clustering of breakpoints. We also evaluated the sensitivity of MLPA in identifying deletions in a mosaic state. Furthermore, we tested whether the MLPA P122 NF1 area assay could distinguish between type I deletions, with breakpoints in low-copy repeats (NF1-LCRs), and type II deletions, caused by aberrant recombination between the JJAZ gene and its pseudogene. Our study showed that intragenic deletions and/or duplications represent only ∼2% of all NF1 mutations. Although MLPA did not substantially increase the mutation detection rate in NF1 patients, it was a useful first step in a comprehensive mutation analysis scheme to quickly pinpoint patients with single- or multiexon deletions/duplications as well as patients with a total gene deletion who will not need full sequencing of the complete coding region. © 2005 Wiley-Liss, Inc.