We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Identification of potential common genetic modifiers of neurofibromas: a genome-wide association study in 1333 patients with neurofibromatosis type 1.
- Authors
Pacot, Laurence; Sabbagh, Audrey; Sohier, Pierre; Hadjadj, Djihad; Ye, Manuela; Boland-Auge, Anne; Bacq-Daian, Delphine; Laurendeau, Ingrid; Briand-Suleau, Audrey; Deleuze, Jean-François; Margueron, Raphaël; Vidaud, Michel; Ferkal, Salah; Parfait, Béatrice; Vidaud, Dominique; Network, the NF-France; Pasmant, Eric; Wolkenstein, Pierre
- Abstract
Background Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumours: cutaneous (cNFs), subcutaneous (scNFs) and plexiform (pNFs) neurofibromas. Objectives To identify neurofibroma modifier genes, in order to develop a database of patients with NF1. Methods All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1333 patients with NF1 who were genotyped for > 7 million common variants. Results A genome-wide association case-only study identified a significant association with 9q21.33 in the pNF phenotype in the discovery cohort. Twelve, three and four regions suggestive of association at the P ≤ 1 × 10–6 threshold were identified for pNFs, cNFs and scNFs, respectively. Evidence of replication was observed for 4, 2 and 6 loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS–mitogen-activated protein kinase pathway, cell-cycle control and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNF and scNF candidate modifiers, as their inactivation specifically affected NF1 -mutant Schwann cell growth. Conclusions Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will, hopefully, contribute to the development of personalized care for patients with this deleterious and life-threatening condition.
- Subjects
GENOME-wide association studies; NEUROFIBROMATOSIS 1; INDIVIDUALIZED medicine; SCHWANN cells; PROTEIN kinases; SKIN innervation
- Publication
British Journal of Dermatology, 2024, Vol 190, Issue 2, p226
- ISSN
0007-0963
- Publication type
Article
- DOI
10.1093/bjd/ljad390