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.

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).