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Genotype-phenotype correlations
Original Article
Genetic Severity Score predicts clinical phenotype in NF2
  1. Dorothy Halliday1,2,
  2. Beatrice Emmanouil2,
  3. Pieter Pretorius3,
  4. Samuel MacKeith4,
  5. Sally Painter5,
  6. Helen Tomkins6,
  7. D Gareth Evans7,
  8. Allyson Parry2,8
  1. 1 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK
  2. 2 Oxford NF2 Unit, Neurosciences, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  3. 3 Department of Neuroradiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  4. 4 Department of ENT, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  5. 5 Department of Ophthalmology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  6. 6 Department of Neurology, Derriford Hospital, Plymouth, Plymouth, UK
  7. 7 Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, Greater Manchester, UK
  8. 8 Nuffield Department of Neurosciences, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  1. Correspondence to Dr Dorothy Halliday, Oxford Centre for Genomic Medicine, Nuffield Orthopaedic Hospital, Windmill Rd, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; dorothy.halliday{at}ouh.nhs.uk

Abstract

​Background The clinical severity of disease in neurofibromatosis type 2 (NF2) is variable. Patients affected with a constitutional truncating NF2 mutation have severe disease, while missense mutations or mosaic mutations present with a milder attenuated phenotype. Genotype-derived natural history data are important to inform discussions on prognosis and management.

Methods We have assessed NF2 clinical phenotype in 142 patients in relation to the UK NF2 Genetic Severity Score to validate its use as a clinical and research tool.

Results The Genetic Severity Score showed significant correlations across 10 measures, including mean age at diagnosis, proportion of patients with bilateral vestibular schwannomas, presence of intracranial meningioma, spinal meningioma and spinal schwannoma, NF2 eye features, hearing grade, age at first radiotherapy, age at first surgery and age starting bevacizumab. In addition there was moderate but significant correlation with age at loss of useful hearing, and weak but significant correlations for mean age at death, quality of life, last optimum Speech Discrimination Score and total number of major interventions. Patients with severe disease presented at a younger age had a higher disease burden and greater requirement of intervention than patients with mild and moderate disease.

Conclusions This study validates the UK NF2 Genetic Severity Score to stratify patients with NF2 for both clinical use and natural history studies.

  • Neurofibromatosis type 2
  • genotype
  • phenotype

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/jmedgenet-2017-104519

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    Footnotes

    • DGE and AP contributed equally.

    • Contributors DH: Study design, acquisition, analysis and interpretation of data and drafting the manuscript. BE: Acquisition, analysis and interpretation of data, revising manuscript critically for intellectual content. PP, SM, SP: Acquisition of data and revising manuscript critically for intellectual content. HT: Acquisition, analysis and interpretation of data. DGE: Interpretation of data and revising manuscript critically for intellectual content. AP: Study design, analysis and interpretation of data, and revising manuscript critically for intellectual content.

    • Competing interests DGE reports personal fees from Astrazeneca, outside the submitted work.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval Study registered as a service evaluation with Oxford University Hospitals Foundation Trust. Registration number: 4406.

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