Emerging genotype–phenotype relationships in patients with large NF1 deletions

Abstract

The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16–26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8–13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype–phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

The biology of cutaneous neurofibromas

“…The first 2 exceptions are specific NF1 gene mutations that result in a very low incidence of cNF or pNF (c.2970-2972delAAT; p.992delM 34 and R1809 NF1 mutations 35 ) and the third results in a higher likelihood of early development and higher number of cNF (large NF1 gene deletions). 36 It would be highly informative to validate the biochemical and biological consequences of mutated neurofibromin to better understand how these first 2 mutations "suppress" cNF development. Specifically, how do these changes alter 3D protein structure, influence sites for binding partners, or affect subcellular localization of neurofibromin?…”

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

“…NF1 microduplications were detected in 14 unrelated individuals identified among a total of 77,902 patients who were investigated by array-CGH due to developmental delay [Moles et al, 2012;Coe et al, 2014;Kehrer-Sawatzki et al, 2017]. Similar to other genomic disorders, this fact could be explained by the presence of heterogeneous clinical phenotypes and an apparently healthy parent often sharing the same microduplication.…”

Genotype‐phenotype correlation in type 1 neurofibromatosis: pMet992del mutation and milder disease

“…NF1 is located on chromosome 17q11.2, is 287‐kb in size, and comprises 57 constitutive and 3 alternatively spliced exons. In the majority of patients, mutations within the boundaries of the NF1 gene cause NF1 . More than 1000 different mutations have been reported.…”