Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1)

Ludwine M Messiaen (1) , Julia Vogt (2) , Kathrin Bengesser (2) , Chuanhua Fu (1) , Fady Mikhail (1) , Eduard Serra (3) , Carles Garcia-Linares (3) , David N. Cooper (4) , Conxi Lázaro (5) , Hildegard Kehrer-Sawatzki (6)

1 Department of Genetics
2 Human Genetics
3 Hereditary Cancer Program
4 Institute of Medical Genetics, College of Medicine
5 Translational Research Laboratory
6 Universität Ulm - Ulm University [Ulm, Allemagne]

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 harbouring 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 4 were putatively type-1, and three were atypical. Two of the 4 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 non-allelic 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.

Mots clés: Life Sciences

Ludwine M Messiaen, Julia Vogt, Kathrin Bengesser, Chuanhua Fu, Fady Mikhail, et al.. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Human Mutation, 2011, 32 (2), pp.213. ⟨10.1002/humu.21418⟩. ⟨hal-00612010⟩