Project 467359

Neurodevelopmental disorders (NDDs) are a major public health problem worldwide, affecting more than 3% of children. These past years, an increasing number of variants in genes encoding proteins of the ubiquitin-proteasome system (UPS) has been identified in patients with NDD. The UPS is a major protein degradation pathway, which is essential to neuronal development and function. Yet, there are still no reliable biological markers or cell/animal models that can be used for diagnostic purposes in patients with such disorders. We have conceived the UPS-NDDiag project to address this shortcoming. Our main objective is to develop tools and a method likely to help diagnose this group of rare diseases. Thanks to an international collaborative effort, we collected and stored, in a dedicated biobank, biological samples of 67 patients with UPS-NDD, and we gathered related photos and clinical information that will be managed in a patient registry hosted by GestaltMatcher. Using simultaneously blood T cells, induced pluripotent stem cell (iPSC)-derived neuronal cell models and animal models, we will search for biological markers, molecular or epigenetic signatures, and morphological and phenotypic features specific to UPS-NDDs, thus relying on our promising preliminary data that suggested overlapping pathophysiological mechanisms across UPS-NDDs. In parallel, we will keep including additional patients whose samples will be used to assess the diagnostic value of highlighted biomarkers, signatures and cell features.