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A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype–phenotype correlations
  1. Saba Sharif1,
  2. Meena Upadhyaya2,
  3. Rosalie Ferner3,
  4. Elisa Majounie2,
  5. Andrew Shenton4,
  6. Michael Baser4,
  7. Nalin Thakker4,
  8. D Gareth Evans4
  1. 1Department of Clinical Genetics, West Midlands Regional Genetics Unit, Birmingham, UK
  2. 2Institute of Medical Genetics, Cardiff University, Cardiff, UK
  3. 3Department of Neurology, GSTT, Guys Hospital, London, UK
  4. 4Manchester Academic Health Science Centre, Genetic Medicine, 6th Floor, St Mary's Hospital, CMFT, Oxford Rd, Manchester, UK
  1. Correspondence to Professor D Gareth Evans, Manchester Academic Health Science Centre, Genetic Medicine, 6th Floor, St Mary's Hospital, Central Manchester University Foundation Trust, Oxford Rd, Manchester, UK; gareth.evans{at}


Background Neurofibromatosis type 1 (NF1) affects 1 in 2500 people, 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 patients with NF1 OPGs, the authors assessed genotype–phenotype correlation. Fluorescein in situ hybridisation was performed to identify large deletions, and then a full gene screen for mutations, by denaturing high-performance liquid chromatography.

Results 80 patients with NF1 OPGs were identified, and molecular analyses were performed in a subset of 29. A clustering of pathogenic changes in the 5′ tertile of the gene was found. The authors combined these results with those for another two NF1 OPG cohorts and collectively found the same trend. When compared with a control population of NF1 patients without an OPG, the OR of a mutation being present in the 5′ tertile 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.

  • NF1
  • OPG
  • genotype
  • phenotype
  • clinical genetics
  • molecular genetics
  • neurology
  • screening
  • other ophthalmology

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  • Andrew Shenton and Mike Baser are both deceased.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Manchester 02/CM/432, Guys 03/02/13.

  • Provenance and peer review Not commissioned; externally peer reviewed.