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Differential rates of germline heterozygote and mosaic variants in NF2 may show varying propensity for meiotic or mitotic mutation
  1. D Gareth Evans1,
  2. George J Burghel2,
  3. Miriam Jane Smith3
  1. 1Division of Evolution and Genomic Science, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, UK
  2. 2Genomic Diagnostic Laboratory, Manchester University NHS Foundation Trust, Manchester, UK
  3. 3Genetic Medicine, University of Manchester, Manchester, UK
  1. Correspondence to Professor D Gareth Evans, Division of Evolution and Genomic Science, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester M13 9WL, UK; gareth.evans{at}mft.nhs.uk

Abstract

NF2-related schwannomatosis is an autosomal dominant tumour predisposition condition that causes multiple benign tumours of the nervous system, especially schwannomas. This results from germline pathogenic variants in the NF2 gene, which are most commonly de novo NF2 nonsense variants. Over half of these de novo variants occur at just six CpG dinucleotides. In this study, we show that the six NF2 CpG nonsense variants make up 54% (136/252) of de novo nonsense variants, despite constituting <10% of nonsense positions in the germline (total=62), and that this pattern is different from the APC gene, which is also known to have a high rate of mosaicism. In addition, the NF2 c.586C>T; p.(Arg196Ter) has a higher de novo heterozygote to mosaicism ratio than the five other CpG variants (73.1% vs 53.7%, p=0.03) and the neighbouring CpG variant (NF2 c.592C>T; p.(Arg198Ter) 38.5%, p=0.02). This may be due to differences in rates of mutation at meiosis versus mitosis.

  • Gene Frequency
  • Germ-Line Mutation

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Footnotes

  • Twitter @BurghelG

  • Collaborators N/a.

  • Contributors Conceptualisation, formal analysis, writing (original draft): DGE; funding acquisition: DGE and MJS; review of variant classifications: MJS and GJB; writing (review and editing): all authors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests DGE is an National Institute for Health Research senior investigator.

  • 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.