A molecular analysis of individuals with Neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations.
Résumé
Background. Neurofibromatosis type 1 (NF1) affects 1 in 2500 individuals and 15% of these may develop an optic pathway glioma (OPG). OPGs behave differently in NF1 and given their frequency surveillance is important. However, this is difficult because of the additional complications these patients may have, such as learning difficulties. Management is also different given that NF1 results from loss of function of tumour suppressor gene. A genotype-phenotype correlation may help to determine who is at risk of developing these tumours, aid focused screening and shed light on response to treatments. Methods As part of a long-term follow up study of NF1 OPGs patients we assessed genotype-phenotype correlation. FISH was performed to identify large deletions and then a full gene screen for mutations, by DHPLC. Results 80 NF1 OPG patients were identified and molecular analyses performed in a subset of 29. We found a clustering of pathogenic changes in the 5' tertile of the gene. We combined our results with another two NF1 OPG cohorts and collectively we saw the same trend. When compared to a control population of NF1 patients without an OPG the odds ratio of a mutation being present in the 5' tercile was 6.05 (p=0.003) in the NF1 OPG combined cohorts. Conclusion It is possible that genotype is a significant determinant of the risk of development of OPGs in NF1.
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