Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome marked by significant clinical heterogeneity. Prior research has primarily focused on mutations within the NF1 gene. This study aimed to conduct a more comprehensive exploration of genotype-phenotype correlations utilizing whole-exome sequencing (WES). Methods: Ten NF1 patients were enrolled. Clinical data were collected, and paired tumor and blood samples underwent WES. Associations between Tumor Mutational Burden (TMB), NF1 and other gene mutations, and clinical phenotypes were analyzed. An NF1-related mutation gene set (N1RMG) was constructed, followed by protein-protein interaction (PPI) network and functional pathway enrichment analyses. Results: In contrast to other genotypes, the germline mutation of NF1 was strongly correlated with the presence of SCNs (p=0.033), while CFAP74 mutations were inversely associated with the presence of spinal NFs (p=0.005). TMB and other genes frequently mutated did not show significant correlations. The N1RMG PPI network was shown to be associated with high levels of direct interactions among NF1 and crucial proteins, including AKT1, BRAF. Functional annotation revealed that N1RMG genes were significantly enriched in biological processes, including myeloid differentiation and endocrine development, as well as in pathways such as chronic myeloid leukemia and endometrial cancer. These pathways eventually feed into the core NF1 signaling axis, RAS/RAF/MEK/ERK and PI3K/AKT/mTOR. Conclusion: NF1 germline mutations and CFAP74 mutations could be predictive factors for a leaner phenotype. NF1 pathogenesis predicts to be a multi-factorial interaction of at least several genes/pathways which together drive the disease process through stimulation of the core RAS and PI3K-mTOR pathway.
Lin et al. (Wed,) studied this question.