Systems Biology Approaches Reveal Potential Phenotype-Modifier Genes in Neurofibromatosis Type 1

Abstract

Neurofibromatosis type (NF1) is a syndrome characterized by varied symptoms, ranging from mild to more aggressive phenotypes. The variation is not explained only by genetic and epigenetic changes in the NF1 gene and the concept of phenotype-modifier genes in extensively discussed in an attempt to explain this variability. Many datasets and tools are already available to explore the relationship between genetic variation and disease, including systems biology and expression data. To suggest potential NF1 modifier genes, we selected proteins related to NF1 phenotype and NF1 gene ontologies. Protein–protein interaction (PPI) networks were assembled, and network statistics were obtained by using forward and reverse genetics strategies. We also evaluated the heterogeneous networks comprising the phenotype ontologies selected, gene expression data, and the PPI network. Finally, the hypothesized phenotype-modifier genes were verified by a random-walk mathematical model. The network statistics analyses combined with the forward and reverse genetics strategies, and the assembly of heterogeneous networks, resulted in ten potential phenotype-modifier genes: AKT1, BRAF, EGFR, LIMK1, PAK1, PTEN, RAF1, SDC2, SMARCA4, and VCP. Mathematical models using the random-walk approach suggested SDC2 and VCP as the main candidate genes for phenotype-modifiers.

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

“…Concerning the specific genotype/phenotype correlation, apart from the whole‐gene deletions, which show the known high frequency of cognitive impairment (Figure 2), 16 the rate of complications or neoplasms presents a wide range (Table 2), regardless of the type of variant (truncating or non‐truncating): for example, the p.Met992del in‐frame deletion, which is expected to generate a milder phenotype, 7 resulted in our study in a breast cancer at 35 years of age. Although breast cancer is part of the neoplastic spectrum of the Neurofibromatosis I disease, 43 the high genetic heterogeneity of this neoplasm does not rule out in the specific case the possible contribution of different genetic predisposition factors or the role of other modifier genes in the phenotypic expression of the disease 44 . Also the data on the p.Arg1947*, which is reported with a milder phenotype, 45 are only partly confirmed, since we have found 2 tumors (one rhabdomyosarcoma at 19 year of age and one hypothalamic astrocytoma at 12) out of the 14 patients harboring the variant.…”

“…Coy number variants are not reported, due to the absence of incident cases in the study population. The shaded areas indicate the 95% confidence intervals contribution of different genetic predisposition factors or the role of other modifier genes in the phenotypic expression of the disease 44.…”

Neurofibromatosis in Children: Actually and Perspectives

“…Pathophysiologically, the disease is characterized by a mutation within the NF1 gene that leads to the absence of neurofibromin, which has a tumor suppressor role, leading to the increased RAS activity and subsequent oncogenic potential [ 63 ]. Therefore, the RAS gene itself or its products may represent potential therapeutic targets in neurofibromatosis via two possible directions: either direct inhibitors of the RAS gene or inhibitors of the products resulting from the modulation pathways of RAS [ 64 , 65 ].…”

Identification of NF1 Frameshift Variants in Two Chinese Families With Neurofibromatosis Type 1 and Early-Onset Hypertension

“…Several large familial NF-1 studies revealed that unlinked modifier genes may influence the expression of the disease ( 36 , 37 ). Recently, using a systems biology strategy, Kowalski et al ( 38 ) identified 10 candidate modifier genes related to the NF-1 phenotype, namely AKT1, BRAF, EGFR, LIMK1, PAK1, PTEN, RAF1, SDC2, SMARCA4 , and VCP . What's more, D'Amico et al ( 39 ) identified that gain-of-function and hypomorphic variants in PTPN11 , a positive regulator of RAS, have been shown to worsen and mitigate, respectively, the severity of the NF1 phenotype.…”