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.
Highlights
Neurofibromatosis type 1 (NF1) is a disease with a worldwide birth incidence of 1 in 2500 and a prevalence of at least 1 in 4000 [1]
Four genotype–phenotype correlations are well described in the literature: NF1 patients harboring microdeletions have been reported to have an increased risk of malignant peripheral nerve sheath tumors, lower average intelligence, connective tissue dysplasia, skeletal malformations, and dysmorphic facial features [7,8,9]; the 3-bp in-frame deletion c.2970_2972delAA was previously associated with absence of neurofibromas [10]; the missense variant p.Arg1809Cys was associated with developmental delay and/or learning disabilities, pulmonic stenosis, and Noonan-like features, but no external plexiform neurofibromas [11]; and missense mutations affecting NF1 codons 844–848 were associated with a more severe clinical presentation [12]
Scheme shows the main steps in chronological order to identity potential NF1 phenotype-modifier genes
Summary
Neurofibromatosis type 1 (NF1) is a disease with a worldwide birth incidence of 1 in 2500 and a prevalence of at least 1 in 4000 [1]. Other less -ommon characteristics are scoliosis, macrocephaly, learning disabilities, plexiform neurofibromas, and multiple other benign and malignant tumors [2,3]. Four genotype–phenotype correlations are well described in the literature: NF1 patients harboring microdeletions have been reported to have an increased risk of malignant peripheral nerve sheath tumors, lower average intelligence, connective tissue dysplasia, skeletal malformations, and dysmorphic facial features [7,8,9]; the 3-bp in-frame deletion c.2970_2972delAA was previously associated with absence of neurofibromas [10]; the missense variant p.Arg1809Cys was associated with developmental delay and/or learning disabilities, pulmonic stenosis, and Noonan-like features, but no external plexiform neurofibromas [11]; and missense mutations affecting NF1 codons 844–848 were associated with a more severe clinical presentation [12]
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