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Original research
Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria for NF2-related schwannomatosis
  1. Miriam J Smith1,2,
  2. Cristina Perez-Becerril1,2,
  3. Mwee van der Meer1,2,
  4. George J Burghel1,2,
  5. Sarah J Waller2,
  6. Megan Carney2,
  7. Sancha Bunstone2,
  8. Katherine Fryer2,
  9. Naomi L Bowers2,
  10. Claire L Hartley2,
  11. Philip T Smith2,
  12. Scott A Rutherford3,
  13. Simon R Freeman4,
  14. Simon K W Lloyd4,
  15. Omar N Pathmanaban3,5,
  16. Andrew Thomas King3,
  17. Dorothy Halliday6,7,
  18. Chris Duff8,
  19. D Gareth Evans1,2
  1. 1 Division of Evolution, Infection and Genomics, The University of Manchester, Manchester, UK
  2. 2 Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK
  3. 3 Department of Neurosurgery, Salford Royal NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Northern Care Alliance NHS Foundation Trust, Manchester, UK
  4. 4 Department of Otolaryngology Head and Neck Surgery, Northern Care Alliance NHS Foundation Trust, Salford Royal Hospital, Manchester Academic Health Science Centre, Manchester, UK, Manchester, UK
  5. 5 Division of Neuroscience, The University of Manchester, Manchester, UK
  6. 6 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  7. 7 Oxford NF2 Unit, Oxford, UK
  8. 8 Department of Plastic Surgery, Manchester Universities Foundation Trust, Manchester, UK
  1. Correspondence to Dr Miriam J Smith; miriam.smith{at}manchester.ac.uk

Abstract

Background Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2-related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1-related or LZTR1-related SWN.

Methods We assessed the variant detection rates for the three major SWN genes (NF2, LZTR1 and SMARCB1) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2-related SWN at the time of genetic testing.

Results We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS).

Conclusions There were similar proportions of LZTR1, SMARCB1 or mosaic NF2. However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification.

  • Genetics
  • Genetics, Medical
  • Genetic Testing
  • Germ-Line Mutation
  • Loss of Function Mutation

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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Footnotes

  • X @BurghelG

  • Contributors Conception and design: MJS and GE. Acquisition of data: All authors. Analysis and interpretation of data MJS, GJB, SJW and MC. Drafting of the manuscript: MJS. Review and approval of final submission: All authors. MJS is responsible for the overall content and acts a guarantor.

  • Funding This study was supported by the USAMRAA CDMRP Neurofibromatosis Research Program, Investigator-Initiated Research Award (W81XWH1910334) and the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007).

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

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.