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    Study of genetics of neurofibromatosis type 1, a tumor-predisposition disorder

    Principal Investigator

    Eric Pasmant



    Neurofibromatosis type 1 is a complex autosomal dominant disorder showing interindividual variations in the timing of the clinical manifestations and the severity of features. The condition is gradually progressive over the lifetime of an individual, although the specific manifestations, rate of progression and severity of complications vary widely. The main interest of the group is to understand the mechanisms underlying the phenotypic variability and the genetic heterogeneity of NF1 using the NF-France database. We aim at identifying the genetic modifiers of the variable expressivity of NF1 with genome wide approaches. Structural and functional characterization of the role of associated-SNPs will be assessed.


    The group

    • Caroline Silve (DR2, INSERM)
    • Michel Vidaud (PU-PH, Université de Paris)
    • Dominique Lallemand (CRCN, INSERM)
    • Dominique Vidaud (MCU-PH, Université de Paris)
    • Béatrice Parfait (MCU-PH, Université de Paris)
    • Audrey Briand (IR, AP-HP)
    • Ingrid Laurendeau (IE, Université de Paris)
    • Laurence Pacot (PhD student, Université de Paris)


    Research interests

    NF1 is one of the most frequent human autosomal dominant Mendelian disease. Fifteen to twenty thousand individuals are affected in France. NF1 is a tumor predisposition syndrome resulting from constitutional heterozygous mutations of the NF1 gene located at 17q11.2 and encoding neurofibromin, a RAS-MAPK pathway inhibitor.

    Thanks to 3 consecutive national funding (Programmes Hospitaliers de Recherche Clinique, PHRC: 2002, 2005, and 2010), a large NF1 cohort (>1,500 NF1 patients) was built in France in collaboration with Pr. Pierre Wolkenstein (Paris Est Créteil University).

    Our previous results based on the NF-France cohort analysis provided evidence that genetic modifiers, unlinked to the NF1 locus, contributed to NF1 variable expressivity. Using a targeted family-based association test, we identified a genetic modifier of neurofibroma development: the large non-coding RNA ANRIL (Pasmant et al. J Natl Cancer Inst. 2011).

    Taking advantage of the NF France cohort, we are conducting an association study at the genome wide level (GWAS). For each NF1 patient, the phenotype was recorded using a standardized questionnaire (eCRF) and the NF1 genotype was determined in link with the hospital activity of the team members: the Genetics Department (Head: Pr. Michel Vidaud) of the Cochin hospital is the NF French reference laboratory. This GWAS project is carried out in collaboration with the French National Genotyping Center (director: Jean-François Deleuze), and the Neurofibromatosis Reference Center (coordinator: Pr. Pierre Wolkenstein): 1,500 NF1 patients will be genotyped using the Human Omni Express Bead Chip array (Illumina). Genotyping data will be analyzed in collaboration with Dr. Audrey Sabbagh (IDR 216, Paris University). Functional characterization of the associated SNPs will be implemented following this GWAS study, notably through cellular approaches.

    We also aim to study bone abnormalities associated with NF1 and the involvement of the periosteum in their occurrence, by conducting genetic and cellular approaches using bone samples from NF1 patients, in collaboration with Dr. Céline Colnot's team (Institut Mondor de Recherche Biomédicale, Créteil).


    Main publications

    • Pacot L, Burin des Roziers C, Laurendeau I, Briand-Suleau A, Coustier A, Mayard T, Tlemsani C, Faivre L, Thomas Q, Rodriguez D, Blesson S, Dollfus H, Muller YG, Parfait B, Vidaud M, Gilbert-Dussardier B, Yardin C, Dauriat B, Derancourt C, Vidaud D, Pasmant E. One NF1 Mutation may Conceal Another. Genes (Basel) 2019;10(9):633.
    • Gruber A, Pacault M, El Khattabi LA, Vaucouleur N, Orhant L, Bienvenu T, Girodon E, Vidaud D, Leturcq F, Costa C, Letourneur F, Anselem O, Tsatsaris V, Goffinet F, Viot G, Vidaud M, Nectoux J. Non-invasive prenatal diagnosis of paternally inherited disorders from maternal plasma: detection of NF1 and CFTR mutations using droplet digital PCR. Clin Chem Lab Med. 2018;56(5):728-738.
    • Fisher MJ, Belzberg AJ, de Blank P, De Raedt T, Elefteriou F, Ferner RE, Giovannini M, Harris GJ, Kalamarides M, Karajannis MA, Kim A, Lázaro C, Le LQ, Li W, Listernick R, Martin S, Morrison H, Pasmant E, Ratner N, Schorry E, Ullrich NJ, Viskochil D, Weiss B, Widemann BC, Zhu Y, Bakker A, Serra E. 2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Am J Med Genet A. 2018;176(5):1258-1269.
    • Santoro C, Di Rocco F, Kossorotoff M, Zerah M, Boddaert N, Calmon R, Vidaud D, Cirillo M, Cinalli G, Mirone G, Giugliano T, Piluso G, D'Amico A, Capra V, Pavanello M, Cama A, Nobili B, Lyonnet S, Perrotta S. Moyamoya syndrome in children with neurofibromatosis type 1: Italian-French experience. Am J Med Genet A. 2017;173(6):1521-1530.
    • Pasmant E, Vidaud D. Neurofibromatosis Type 1 Molecular Diagnosis: The RNA Point of View. EBioMedicine 2016;7:21-2.
    • Pasmant E, Parfait B, Luscan A, Goussard P, Briand-Suleau A, Laurendeau I, Fouveaut C, Leroy C, Montadert A, Wolkenstein P, Vidaud M, Vidaud D. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet. 2015;23:596-601.
    • Pasmant E, Gilbert-Dussardier B, Petit A, de Laval B, Luscan A, Gruber A, Lapillonne H, Deswarte C, Goussard P, Laurendeau I, Uzan B, Pflumio F, Brizard F, Vabres P, Naguibvena I, Fasola S, Millot F, Porteu F, Vidaud D, Landman-Parker J, Ballerini P. SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. Oncogene 2015;34:631-8.
    • Imbard A, Pasmant E, Sabbagh A, Luscan A, Soares M, Goussard P, Blanché H, Laurendeau I, Ferkal S, Vidaud M, Pinson S, Bellanne-Chantelot C, Vidaud D, Wolkenstein P; members of the NF France Network, Parfait B. NF1 single and multi-exons copy number variations in neurofibromatosis type 1. J Hum Genet. 2015;60(4):221-4.


    Financial supports

    These programs are supported by ANR 2018 grant, Projet PERISTEM in collaboration with Dr. Céline Colnot and by the CAP NF Foundation.