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

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 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 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.

Characterization of the Phenotype Associated with Microduplication Reciprocal to <b><i>NF1 </i></b>Microdeletion Syndrome

“…Moreover, the brain MRI performed at 7 years of age did not reveal optic pathway gliomas or any other tumours, or unidentified bright objects. These data therefore confirm that NF1 duplications are not associated with any of the characteristic signs of neurofibromatosis type 1 [Kehrer-Sawatzki et al, 2014].…”

“…Duplications encompassing the NF1 gene have been reported so far in 17 individuals with variable phenotypes. Most of these individuals presented a nonspecific clinical phenotype characterized by developmental delay, intellectual disability, and facial dysmorphisms, while some parents harbouring the same microduplication appeared to be entirely healthy or affected [Lu et al, 2007;Grisart et al, 2008;Moles et al, 2012;Kehrer-Sawatzki et al, 2014].…”

Emerging genotype–phenotype relationships in patients with large NF1 deletions

“…Only two of the 29 NF1 microduplication carriers had CALS. However, these CALS were atypical, with irregular borders and nonhomogeneous pigmentation which is not generally characteristic of those CALS typically seen in patients with NF1 (Kehrer-Sawatzki et al 2014). One of the two NF1 microduplication patients with CALS fulfilled the diagnostic criteria for NF1 because he not only had ten CALS but also Lisch nodules.…”

“…So far, 29 NF1 microduplication carriers have been reported, 18 of them were unrelated cases (Lu et al. 2007; Grisart et al 2008; Moles et al 2012; Coe et al 2014; Kehrer-Sawatzki et al 2014). None of the individuals with an NF1 microduplication so far reported exhibited neurofibromas or other NF1-associated tumours.…”

“…Furthermore, it could not be excluded that somatically acquired NF1 mutations in melanocyte progenitor cells contributed to the occurrence of CALS and Lisch nodules in this individual. Since melanocytes from CALS of this patient could not be investigated, his clinical manifestations are difficult to interpret with regard to the underlying mutation (Kehrer-Sawatzki et al 2014). Nevertheless, the analysis of the other 28 NF1 microduplication carriers reported to date implies that these duplications do not cause a classical NF1 phenotype.…”