Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

Hum Mutat. 2021 Oct;42(10):1187-1207. doi: 10.1002/humu.24261. Epub 2021 Jul 29.


Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non-mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non-NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%-86% of familial cases and 30%-40% of non-NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.

Keywords: intronic; neurofibromatosis; noncoding; pathogenic variants; regulatory; schwannomatosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Humans
  • MicroRNAs*
  • Neurilemmoma* / diagnosis
  • Neurilemmoma* / genetics
  • Neurilemmoma* / pathology
  • Neurofibromatoses* / diagnosis
  • Neurofibromatoses* / genetics
  • Neurofibromatoses* / pathology
  • Neurofibromatosis 1* / diagnosis
  • Neurofibromatosis 1* / genetics
  • RNA-Binding Proteins
  • SMARCB1 Protein
  • Skin Neoplasms* / genetics
  • Transcription Factors / genetics


  • DGCR8 protein, human
  • LZTR1 protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors

Supplementary concepts

  • Schwannomatosis