Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I

Matteo Riva, Davide Martorana, Vera Uliana, Edoardo Caleffi, Elena Boschi, Livia Garavelli, Giovanni Ponti, Luca Sangiorgi, Claudio Graziano, Stefania Bigoni, Luca Maria Rocchetti, Simona Madeo, Fiorenza Soli, Enrico Grosso, Diana Carli, Matteo Goldoni, Francesco Pisani, Antonio Percesepe

Research output: Contribution to journalArticlepeer-review


Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re-evaluated the NF1 gene variants found in the period 2000–2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2–11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non-homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5′ end of NF1 had a lower age-related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5′ end of the NF1 gene although not significant at the multivariate analysis.

Original languageEnglish
JournalGenes Chromosomes and Cancer
Issue number1
Publication statusE-pub ahead of print - Aug 24 2021


  • genotype/phenotype
  • Neurofibromatosis type I
  • NF1 gene pathogenic variants

ASJC Scopus subject areas

  • Genetics
  • Cancer Research


Dive into the research topics of 'Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I'. Together they form a unique fingerprint.

Cite this