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Genotype-phenotype associations in neurofibromatosis type 1 (NF1): an increased risk of tumor complications in patients with NF1 splice-site mutations?

Adila Alkindy1, Nadia Chuzhanova2, Usha Kini3, David N Cooper4 and Meena Upadhyaya4*

Author Affiliations

1 Clinical Genetics Department, Sultan Qaboos University Hospital, P.O. Box 39, Al-Khod, Muscat 123, Sultanate of Oman

2 School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK

3 Department of Clinical Genetics, Churchill Hospital, Old Road Headington, Oxford, OX3 7LJ, UK

4 Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK

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Human Genomics 2012, 6:12  doi:10.1186/1479-7364-6-12

Published: 13 August 2012


Neurofibromatosis type 1 (NF1) is a complex neurocutaneous disorder with an increased susceptibility to develop both benign and malignant tumors but with a wide spectrum of inter and intrafamilial clinical variability. The establishment of genotype-phenotype associations in NF1 is potentially useful for targeted therapeutic intervention but has generally been unsuccessful, apart from small subsets of molecularly defined patients. The objective of this study was to evaluate the clinical phenotype associated with the specific types of NF1 mutation in a retrospectively recorded clinical dataset comprising 149 NF1 mutation-known individuals from unrelated families. Each patient was assessed for ten NF1-related clinical features, including the number of café-au-lait spots, cutaneous and subcutaneous neurofibromas and the presence/absence of intertriginous skin freckling, Lisch nodules, plexiform and spinal neurofibromas, optic gliomas, other neoplasms (in particular CNS gliomas, malignant peripheral nerve sheath tumors (MPNSTs), juvenile myelomonocytic leukemia, rhabdomyosarcoma, phaechromocytoma, gastrointestinal stromal tumors, juvenile xanthogranuloma, and lipoma) and evidence of learning difficulties. Gender and age at examination were also recorded. Patients were subcategorized according to their associated NF1 germ line mutations: frame shift deletions (52), splice-site mutations (23), nonsense mutations (36), missense mutations (32) and other types of mutation (6). A significant association was apparent between possession of a splice-site mutation and the presence of brain gliomas and MPNSTs (p = 0.006). If confirmed, these findings are likely to be clinically important since up to a third of NF1 patients harbor splice-site mutations. A significant influence of gender was also observed on the number of subcutaneous neurofibromas (females, p = 0.009) and preschool learning difficulties (females, p = 0.022).

Neurofibromatosis type 1; Genotype-phenotype correlation; Malignant peripheral nerve sheath tumors; Brain glioma; Increased cancer susceptibility; Splice-site mutations; NF1 gene; Gender effect