Identification of potential common genetic modifiers of neurofibromas: a genome wide association study in 1,333 neurofibromatosis type 1 patients - CEA - Commissariat à l’énergie atomique et aux énergies alternatives Accéder directement au contenu
Article Dans Une Revue The British journal of dermatology Année : 2023

Identification of potential common genetic modifiers of neurofibromas: a genome wide association study in 1,333 neurofibromatosis type 1 patients

Résumé

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.
Fichier non déposé

Dates et versions

cea-04334212 , version 1 (10-12-2023)

Identifiants

Citer

Laurence Pacot, Audrey Sabbagh, Pierre Sohier, Djihad Hadjadj, Manuela Ye, et al.. Identification of potential common genetic modifiers of neurofibromas: a genome wide association study in 1,333 neurofibromatosis type 1 patients. The British journal of dermatology, 2023, ⟨10.1093/bjd/ljad390⟩. ⟨cea-04334212⟩
16 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More