Related Experiment Video
Updated: Jun 4, 2026
Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models
Published on: May 17, 2024
Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1)
Ludwine Messiaen1, Julia Vogt, Kathrin Bengesser
1Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Abstract:
Mosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harboring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisposition syndrome and the frequency of mosaicism. Seven of the 14 mosaic NF1 deletions were type-2, whereas four were putatively type-1, and three were atypical. Two of the four probable type-1 deletions were confirmed as such by breakpoint-spanning PCR or SNP analysis. Both deletions were associated with a generalized manifestation of NF1. Independently, we identified a third patient with a mosaic type-1 NF1 deletion who exhibited segmental NF1. Together, these three cases constitute the first proven mosaic type-1 deletions so far reported. In two of these three mosaic type-1 deletions, the breakpoints were located within PRS1 and PRS2, previously identified as hotspots for nonallelic homologous recombination (NAHR) during meiosis. Hence, NAHR within PRS1 and PRS2 is not confined to meiosis but may also occur during postzygotic mitotic cell cycles.
Insights
Mosaicism in neurofibromatosis type 1 (NF1) is common, especially with large deletions. This study confirms the first proven mosaic NF1 deletions, suggesting a link between mutation rates and mosaicism frequency.
Area of Science:
- Genetics
- Molecular Biology
- Human Diseases
Background:
- Mosaicism, the presence of genetically distinct cell lines within an individual, is a significant factor in neurofibromatosis type 1 (NF1).
- It influences NF1's clinical presentation and the risk of transmission to offspring.
- Understanding mosaicism is crucial for accurate diagnosis and genetic counseling in NF1.
Purpose of the Study:
- To investigate the frequency and characteristics of mosaicism in patients with large NF1 deletions.
- To identify and confirm cases of mosaic type-1 NF1 deletions.
- To explore the mechanisms underlying mosaic NF1 deletions.
Main Methods:
- Screening of 3500 NF1 patients using Fluorescence In Situ Hybridization (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA).
- Identification of gross NF1 deletions and assessment for somatic mosaicism.
- Breakpoint analysis using breakpoint-spanning PCR and SNP analysis for confirmation.
Main Results:
- 146 out of 3500 NF1 patients harbored gross NF1 deletions, with 14 (9.6%) exhibiting somatic mosaicism.
- Seven mosaic deletions were type-2, four were putatively type-1, and three were atypical.
- Three cases of mosaic type-1 NF1 deletions were confirmed, with breakpoints in known hotspots for nonallelic homologous recombination (NAHR).
Conclusions:
- Mosaicism is frequent in NF1 patients with large deletions, supporting a link between high mutation rates and mosaicism.
- This study reports the first confirmed cases of mosaic type-1 NF1 deletions.
- NAHR within specific regions (PRS1 and PRS2) can occur during postzygotic mitotic cell cycles, not just meiosis.
