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

Abstract

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 0 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 0 end of the NF1 gene although not significant at the multivariate analysis.

Mutation analysis and clinical profile of South African patients with Neurofibromatosis type 1 (NF1) phenotype

“…Variants in these protein domains are reported to affect the protein activity, leading to loss of function of the neurofibromin protein due to haploinsufficiency ( Bergoug et al, 2020 ; Zhang et al, 2021 ). The distribution of the variants in the NF1 gene protein domains is similar to the one observed in the literature where distribution of various pathogenic variant types throughout the gene with no obvious hotspot region ( Friedman, 1993b ; Abdel-Aziz et al, 2021 ; Legius et al, 2021 ; Riva et al, 2022 ). Missense variants were observed to cluster in the CSRD domain ( Figure 1 ) with no truncating variant observed, however the sample size in the current study is too small to make significant discussion on these.…”

“…The high frequency of truncating variants compared to the missense variants was not unique to the present study. In a study by Riva et al, 2022 that reviewed NF1 patient records in Parma hospital in Italy, out of 34 variants identified, 67.6% (23) were frameshift and nonsense compared to one missense variant ( Riva et al, 2022 ). Although there are no significant differences in phenotype severity reported between truncating and missense NF1 variants in the literature as well as the current cohort, a study on NF1 missense variants ( Koczkowska et al, 2020 ) showed that some patients with these variants exhibited some Noonan syndrome phenotypes such as pulmonic stenosis, cardiovascular abnormalities, short stature and macrocephaly.…”

Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors

“…In recent years, more than 3000 different genetic variants in the NF1 gene have been reported, and most of them lead to loss of expression or synthesis of non-functional neurofibromin [78]. This increase in the amount of genetic data has led to numerous studies aimed at NF1 genotype-phenotype correlation [79][80][81][82][83]. Some of these studies reported agedependent manifestations of some cancers like optic pathway gliomas that are associated with younger pediatric NF1 patients [84].…”

Schwann cells modulate nociception in neurofibromatosis 1

“…NF1 is characterized by loss of the Nf1 gene which produces neurofibromin, a negative regulator of Ras-GTP signaling that modulates cell growth [22][23][24]. There are mutations in both Nf1 alleles in neurofibromas and neurofibroma SCs [11,[25][26][27][28]. Complete Nf1 loss of function in SCs correlates with neurofibroma formation.…”