Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic disorders caused by dysfunctions of the immune system. SAIDs are characterized by excessive and uncontrolled inflammation that can affect many organs and tissues. Recent advances in next-generation sequencing technologies have led to the identification of an increasing number of genes and variants associated with these diseases. However, interpreting genetic findings and linking them to clinical symptoms remains complex because patients carrying the same genetic variant may present highly variable manifestations, even within the same family.
This project aims to improve the diagnosis and understanding of SAIDs through the integration of clinical, genetic, bioinformatic, and functional data. The consortium combines expertise from international registries, clinical immunology, genetics, bioinformatics, and functional immunology.
The project focuses on three main objectives:
- Improving and validating the use of Human Phenotype Ontology (HPO)* terms for the accurate classification of SAIDs and optimization of genotype–phenotype analysis through the transfer and integration of Eurofever clinical data with standardized HPO coding.
- Investigating the mechanisms underlying intra-familial variability and discrepancies between genetic findings and clinical presentation using innovative technological approaches such as polygenic risk score (PRS) analysis, methylomics, and transcriptomic signatures.
- Developing a coordinated strategy for the functional characterization of variants of unknown significance (VUS) and unclassified variants associated with SAIDs.
Significant progress has already been achieved through the transcoding of 222 clinical variables into standardized HPO terms within the Eurofever registry (WP1). In parallel, clinical and genetic data from 69 patients have been collected and integrated to perform polygenic risk score analyses as well as transcriptomic and methylomic profiling (WP2). Furthermore, the results of functional studies on NLRP3 and NLRP1 gene variants have been made publicly available to the scientific community through the Infevers database.
The project is contributing to the harmonization of phenotypic and genetic data analysis and to the development of innovative approaches for variant interpretation. The expected results of the project include improved diagnostic accuracy, better interpretation of genetic variants, enhanced disease classification, and more personalized therapeutic strategies for patients with systemic autoinflammatory diseases. Ultimately, the project aims to support earlier diagnosis and better clinical management of patients affected by these rare and complex immune disorders.
* Human Phenotype Ontology (HPO) is a standardized vocabulary used to describe the clinical signs and symptoms observed in patients with genetic or rare diseases. Each symptom is associated with a precise and internationally recognized code, allowing clinicians and researchers to describe patient phenotypes in a harmonized way and to improve the analysis of genotype–phenotype correlations.