title: Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients.
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 approximately 95% in NF1 patients. The majority of mutations are minor lesions, and approximately 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 approximately 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.
authors.affiliation: Laboratory Medical Genomics, Department of Genetics UAB, University of Alabama at Birmingham, 35249-0024, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wimmer
authors.forename: S
authors.initials: S
authors.lastname: Yao
authors.forename: K
authors.initials: K
authors.lastname: Claes
authors.forename: H
authors.initials: H
authors.lastname: Kehrer-Sawatzki
authors.forename: S
authors.initials: S
authors.lastname: Tinschert
authors.forename: T
authors.initials: T
authors.lastname: De Raedt
authors.forename: E
authors.initials: E
authors.lastname: Legius
authors.forename: T
authors.initials: T
authors.lastname: Callens
authors.forename: H
authors.initials: H
authors.lastname: Beiglböck
authors.forename: O
authors.initials: O
authors.lastname: Maertens
authors.forename: L
authors.initials: L
authors.lastname: Messiaen
mesh_terms: D005091:Exons; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques; D011544:Pseudogenes; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D025542:Neurofibromin 1; D014157:Transcription Factors