Identification of Large NF1 Duplications Reciprocal to NAHR-Mediated Type-1 NF1 Deletions
Kehrer-Sawatzki, Hildegard × Bengesser, Kathrin Callens, Tom Mikhail, Fady Fu, Chuanhua Hillmer, Morten Walker, Martha E Saal, Howard M Lacassie, Yves Cooper, David N Messiaen, Ludwine #
Human mutation vol:35 issue:12 pages:1469-75
Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only 9 unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harboured the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the 9 NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high resolution breakpoint analysis which indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot PRS2, which also harbours the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events. This article is protected by copyright. All rights reserved.