Identification of Large NF1 duplications reciprocal to NAHR-Mediated Type-1 NF1 deletions

Academic Article

Abstract

  • Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple cafĂ© 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 harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine 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 that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors 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. For some recurrent deletion syndromes caused by NAHR, the reciprocal genomic duplications have been identified. In this study, we performed high resolution breakpoint analysis which indicated that the two duplications analysed 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, these NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events.
  • Published In

  • Human Mutation  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 11784717
  • Author List

  • Kehrer-Sawatzki H; Bengesser K; Callens T; Mikhail F; Fu C; Hillmer M; Walker ME; Saal HM; Lacassie Y; Cooper DN
  • Start Page

  • 1469
  • End Page

  • 1475
  • Volume

  • 35
  • Issue

  • 12