Optimization of the diagnostic approach for inborn errors of immunity leading to hyper-inflammation – ODINO

Inborn errors of immunity (IEI) are a large group of genetic conditions that result in an alteration of the normal function of the immune response. Beside the classical primary immunodeficiencies (PID), characterized by an increased susceptibility to infection, other conditions are associated with an over-activation of the immune response, leading to an exaggerate sterile inflammatory reaction. This latter group of conditions are defined as systemic autoinflammatory diseases (SAID).
Aim: to improve the diagnostic approach to IEI, using SAID as proof of concept. We will focus on three critical aspects:
1. Validation in the real world of the accuracy of the new HPO terms for the proper classification of each SAID and optimization of the bioinformatic analysis with the integration of an evidence-based statistical approach.
2. Use of novel technological approaches to unravel the intra-familial phenotypic heterogeneity and genotype-phenotype correlation discrepancies associated to SAIDs, starting from families collected in Eurofever Database
3. Provide a homogeneous and coordinated strategy for the functional characterization of VUS and unclassified variants associated to SAID. Pathogenicity of novel variants in the panels of known SAID-associated gene derived from Infevers database will be assessed by functional strategies.
The whole project will be focused on the integration of in-silico and in-vitro approaches with real-life data coming from a large international registry (Eurofever) and from an online repository of all the variants associated with SAID-related genes (Infevers).