Emerging genotype –phenotype relationships in patients with large NF1 deletions
AbstractThe most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing theNF1 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-1NF1 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-mosaicNF1 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 intragenicNF1 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 theSUZ12 gene in addition toNF1 further increases the ...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research
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