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Original research
NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study
  1. Claire Forde1,
  2. Miriam J Smith2,
  3. George J Burghel3,
  4. Naomi Bowers4,
  5. Nicola Roberts5,
  6. Tim Lavin6,
  7. Jane Halliday7,
  8. Andrew Thomas King7,
  9. Scott Rutherford7,
  10. Omar N Pathmanaban7,
  11. Simon Lloyd8,
  12. Simon Freeman9,
  13. Dorothy Halliday10,11,
  14. Allyson Parry12,
  15. Patrick Axon13,
  16. Juliette Buttimore13,
  17. Shazia Afridi14,
  18. Rupert Obholzer15,
  19. Roger Laitt16,
  20. Owen Thomas17,
  21. Stavros Michael Stivaros18,19,
  22. Grace Vassallo20,
  23. D Gareth Evans21,22
  1. 1Clinical Genetics Service, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  2. 2Genetic Medicine, University of Manchester, Manchester, UK
  3. 3Genomic Diagnostic Laboratory, Manchester University NHS Foundation Trust, Manchester, UK
  4. 4North West Genomic Laboratory Hub, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  5. 5Genomic Medicine, MFT, Manchester, UK
  6. 6Department of Neurology, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK
  7. 7Department of Neurosurgery, Salford Royal Hospital, Salford, UK
  8. 8Department of Otolaryngology, University of Manchester, Manchester, UK
  9. 9Otolaryngology, Salford Royal NHS Foundation Trust, Salford, UK
  10. 10Oxford Centre for Genetic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  11. 11Neurosciences, NF2 Unit, Oxford, UK
  12. 12Department of Neurology, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK
  13. 13Department of Otolaryngology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  14. 14Guy's and St Thomas' Hospitals NHS Trust, London, UK
  15. 15ENT and Skull Base Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK
  16. 16Northern Care Alliance NHS Foundation Trust, Salford, Manchester, UK
  17. 17Department of Neuroradiology, Salford Royal Hospital, Salford, UK
  18. 18Centre for Imaging Sciences, Institute of Population Health, University of Manchester, Manchester, UK
  19. 19Academic Unit of Paediatric Radiology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Academic Health Sciences Centre, Manchester, UK
  20. 20Department of Paediatric Neurology, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  21. 21Neurosurgery, Northern Care Alliance NHS Foundation Trust, Salford, Manchester, UK
  22. 22The University of Manchester, Manchester, UK
  1. Correspondence to Professor D Gareth Evans, The University of Manchester, Manchester M13 9WL, UK; gareth.d.evans{at}manchester.ac.uk

Abstract

Objectives New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed.

Methods The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England’s specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed.

Results 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1-related schwannomatosis and SMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4–18.4 times lower than NF2.

Conclusions This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.

  • Gene Pool
  • Gene Rearrangement
  • Genetic Testing

Data availability statement

Data are available upon reasonable request. Anonymised data can be requested.

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Data availability statement

Data are available upon reasonable request. Anonymised data can be requested.

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Footnotes

  • X @BurghelG

  • Contributors Planning: DGE; conduct: DGE, CF; conception and design: DGE; acquisition of data or analysis: DGE, CF, GJB; interpretation of data: DGE, CF; drafting and approval of final version: all authors. DGE is the guarantor.

  • Funding Manchester National Institute for Health Research Manchester Biomedical Research Centre (NIHR203308).

  • Competing interests DGE has received consultancy fees from AstraZeneca, Springworks and Everything Genetic Ltd.

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