Multiple endocrine neoplasia type 1 (MEN1) is a rare disease caused by mutations in the tumor suppressive gene MEN1. The 3 cardinal lesions are primary hyperparathyroidism, pituitary tumors, and neuroendocrine duodeno-pancreatic tumors. 27 to 70% of MEN1 patients die due to the disease. Despite a very specific phenotype, a large number of sporadic index cases receive a negative or uninformative genetic testing. The identification of mutation is essential to do the diagnosis in patients with an incomplete phenotype, but also to allow genetic counseling in families. Moreover, MEN1 is a long-life treating disease in which the lesions can occurred at any age, with no genotype-phenotype correlation. The disease penetrance is complete, but the phenotypical expression is variable, even within the same family. We reported that patients with MEN1 mosaic mutation have a phenotype as severe as patients with heterozygous mutation Our aim is to improve the diagnosis of MEN1 by developing i) tools to search for unconventional anomalies such as MEN1 mosaicism, promotor and deep-intronic mutation, and ii) functional analysis of sequence variants of uncertain significance. For that, we will use DNA and RNA sequencing of blood samples by next generation sequencing, and we will use a human organoid model of pituitary tumor that we developed in which the VSI will be introduced using Crispr-Cas9. Our second aim is to develop, characterize and compare by using a mosaic disease model, the tumor phenotypes of mouse models with mono- or bi-allelic inactivation of the Men1 gene in neural-crest derived cells at different time points of their pre- and post-natal differentiation. We will study the consequences of MEN1 deficiencies in tissues and the non-cell-autonomous factors that can lead to the development of tumors, in order to better understand the expression variability, and to identify, in very original way, new translational and actionable therapeutic leads.