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 ,   the NF-France Network, Adamski Henri , Baumann-Morel Clarisse , Bellanné Christine , Biet Eric , Bousque Pascal , Brand Christian , Balguerie Xavier , Castelnau Pierre , Chaix Yves , Chevrant-Breton Jacqueline , Collet Evelyne , Cuny Jean-François , Chastagner Pascal , Chandeclerc Marie-Lorraine , Cheuret Emmanuel , Cintas Pascal , Dollfus Helene , Derancourt Christian , Drouin-Garraud Valérie , d’Incan Michel , De Leersnyder Hélène , Dereure Olivier , Doumar Diane , Fabre Nicolas , Ferraro Vincenza , Francannet Christine , Faivre Laurence , Fellmann Florence , Gaillard Nathalie Feugier Dominique , Goldenberg Alice , Guyant-Marechal Lucie , Guillot Bernard , Guillamo Jean-Sebastien , Hadj-Rabia Smaïl , Hamel-Teillac Dominique , Kemlin Isabelle , Lacour Jean-Philippe , Laithier Veronique , Lesavre Nathalie , Lyonnet Stanislas , Maincent Kim , Maradeix Sophie , Machet Laurent , Mansat Eva , Meyer Nicolas , Mozelle Monique , Moret Jean Christophe Moreno Celine , Puzenat Eric , Pinson Stéphane , Rodriguez Diana , Stalder Jean-François , Schweitzer Elisabeth , Thalamas Claire , Thauvin Christel , Verloes Alain , Zeller Jacques , Pasmant Eric , Wolkenstein Pierre 
Published: October 2023

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 &gt; 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.