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Background  Neurofibromatosis type-1 (NF1) is caused by mutations of the  NF1  gene at 17q11.2. In 95% of non-founder NF1 patients,  NF1  mutations are identifiable by means of a comprehensive mutation analysis. 5-10% of these patients harbour microdeletions encompassing the  NF1  gene and its flanking regions. NF1 is characterised by tumours of the peripheral nerve sheaths, the pathognomonic neurofibromas. Considerable inter- and intra-familial variation in expressivity of the disease has been observed which is influenced by genetic modifiers unrelated to the constitutional  NF1  mutation. The number of plexiform neurofibromas (PNF) in NF1 patients is a highly heritable genetic trait. Recently, SNP rs2151280 located within the non-coding RNA gene  ANRIL  at 9p21.3, was identified as being strongly associated with PNF number in a family-based association study. The T-allele of rs2151280, which correlates with reduced  ANRIL  expression, appears to be associated with higher PNF number.  ANRIL  directly binds to the SUZ12 protein, an essential component of polycomb repressive complex 2, and is required for SUZ12 occupancy of the  CDKN2A/CDKN2B  tumour suppressor genes as well as for their epigenetic silencing.    Methods  Here, we explored a potential association of PNF number and PNF volume with SNP rs2151280 in 29 patients with constitutional  NF1  microdeletions using the exact Cochran-Armitage test for trends and the exact Mann–Whitney–Wilcoxon test. Both the PNF number and total tumour volume in these 29 NF1 patients were assessed by whole-body MRI. The  NF1  microdeletions observed in these 29 patients encompassed the  NF1  gene as well as its flanking regions, including the  SUZ12  gene.    Results  In the 29 microdeletion patients investigated, neither the PNF number nor PNF volume was found to be associated with the T-allele of rs2151280.    Conclusion  Our findings imply that, at least in patients with  NF1  microdeletions, PNF susceptibility is not associated with rs2151280. Although somatic inactivation of the  NF1  wild-type allele is considered to be the PNF-initiating event in NF1 patients with intragenic mutations and patients with  NF1  microdeletions, both patient groups may differ with regard to tumour progression because of the heterozygous constitutional deletion of  SUZ12  present only in patients with  NF1  microdeletions.

Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1microdeletions