TY - JOUR
T1 - Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I
AU - Riva, Matteo
AU - Martorana, Davide
AU - Uliana, Vera
AU - Caleffi, Edoardo
AU - Boschi, Elena
AU - Garavelli, Livia
AU - Ponti, Giovanni
AU - Sangiorgi, Luca
AU - Graziano, Claudio
AU - Bigoni, Stefania
AU - Rocchetti, Luca Maria
AU - Madeo, Simona
AU - Soli, Fiorenza
AU - Grosso, Enrico
AU - Carli, Diana
AU - Goldoni, Matteo
AU - Pisani, Francesco
AU - Percesepe, Antonio
N1 - Funding Information:
The authors acknowledge the support by the ?Fondazione Emma ed Ernesto Rulfo per la Genetica Medica? (Italy). This work has been generated within the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. Open Access Funding provided by Universita degli Studi di Parma within the CRUI-CARE Agreement.
Publisher Copyright:
© 2021 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.
PY - 2021/8/24
Y1 - 2021/8/24
N2 - 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.
AB - 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.
KW - genotype/phenotype
KW - Neurofibromatosis type I
KW - NF1 gene pathogenic variants
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U2 - 10.1002/gcc.22997
DO - 10.1002/gcc.22997
M3 - Article
AN - SCOPUS:85114164596
VL - 61
JO - Genes Chromosomes and Cancer
JF - Genes Chromosomes and Cancer
SN - 1045-2257
IS - 1
ER -