Spectrum of single‐ and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients

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Abstract
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.