Identification of potential common genetic modifiers of neurofibromas: a genome-wide association study in 1333 patients with neurofibromatosis type 1

Background: Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumors named cutaneous (cNFs), subcutaneous (scNFs), and plexiform (pNFs) neurofibromas.Objectives: A significant genetic component in the variability of neurofibroma incidence was evidenced, but without the influence of the causative NF1 gene pathogenic variant. To identify neurofibroma modifier genes, a NF1 patient database was developed.Methods: All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1,333 NF1 patients who were genotyped for more than 7 million common variants.Results: Genome-wide association case-only study identified a significant association in 9q21.33 for the pNFs phenotype in the discovery cohort. Twelve, three, and four regions suggestive of association at the 10-6 threshold were identified for pNFs, cNFs, and scNFs, respectively. Evidence of replication was observed for four, two, and six loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS-MAPK pathway, cell cycle control, and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNFs and scNFs candidate modifiers, as their inactivation specifically affected NF1-mutant Schwann cells growth.Conclusion: Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will hopefully contribute to the development of personalized care for this deleterious and life-threatening condition.