Identification of LargeNF1Duplications Reciprocal to NAHR-Mediated Type-1NF1Deletions


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Abstract

Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of theNF1gene region. To date, only nine unrelated cases of largeNF1duplications 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 novelNF1duplications, one sporadic and one familial. Both index patients withNF1duplications 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 theNF1duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nineNF1duplications 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-1NF1deletion breakpoints. Hence, our study indicates for the first time thatNF1duplications are reciprocal to type-1NF1deletions 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.

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