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 compared to 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 towards a lower cancer risk for carriers of variants in the 5' end of the NF1 gene, although not significant at the multivariate analysis This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)10-21
Number of pages12
JournalGenes Chromosomes and Cancer
Issue number1
Publication statusPublished - Jan 2022


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


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