NF1 patient missense variants predict a role for ATM in modifying neurofibroma initiation

Yanan Yu, Kwangmin Choi, Jianqiang Wu, Paul R. Andreassen, Phillip J. Dexheimer, Mehdi Keddache, Hilde Brems, Robert J. Spinner, Jose A. Cancelas, Lisa J. Martin, Margaret R. Wallace, Eric Legius, Kristine S. Vogel, Nancy Ratner

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some neurofibromas. ATM-relevant DNA repair defects were also present in a subset of neurofibromas with ATM variants, and in some neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.

Original languageEnglish (US)
Pages (from-to)157-174
Number of pages18
JournalActa Neuropathologica
Issue number1
StatePublished - Jan 1 2020


  • ATM
  • DNA damage
  • Genomics
  • Modifier genes
  • Mutation
  • Neurofibroma
  • Neurofibromatosis type 1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'NF1 patient missense variants predict a role for ATM in modifying neurofibroma initiation'. Together they form a unique fingerprint.

Cite this