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.