Incidence of mosaicism in 1055 de novo NF2 cases: Much higher than previous estimates with high utility of Next Generation Sequencing.

Research output: Contribution to journalArticle

  • External authors:
  • Claire Hartley
  • Philip T. Smith
  • Andrew T. King
  • Naomi L. Bowers
  • Simon Tobi
  • Andrew J Wallace
  • Mary Perry
  • Raji Anup
  • Simon K.W. Lloyd
  • Scott A. Rutherford
  • Charlotte Hammerbeck-Ward
  • Emma Stapleton
  • Simon Freeman
  • Mark Kellett
  • Dorothy Halliday
  • Allyson Parry
  • Juliette J Gair
  • Patrick R. Axon
  • Roger Laitt
  • Owen Thomas
  • Shazia K Afridi
  • R Obholzer
  • Chris Duff
  • Grace Vassallo


Purpose:To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). Methods:Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n=1055), were tested for NF2 variants in lymphocyte DNA and where available tumour DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next generation sequencing. Results:The rate of proven/presumed mosaicism was 232/1055(22.0%). However, non-mosaic heterozygous pathogenic variants were only identified in 387/1055(36.7%). When mutation detection rates in second generation non-mosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single nucleotide pathogenic NF2 variant. Conclusion:This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is non-lethal in heterozygote form. Risks to offspring are small and probably correlate with mutation allele frequency detected in blood.

Bibliographical metadata

Original languageEnglish
JournalGenetics in Medicine
Publication statusPublished - 5 Jul 2019