| Title: | Search for inborn errors of immunity underlying infectious diseases using whole exome and whole genome sequencing data. |
| Lead Institution: | INSERM |
| Principal investigator: |
Application 98772
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About
Over the last 25 years, we have discovered genetic etiologies of a large number of viral (including COVID-19), bacterial, and fungal diseases. We intend to search for novel IEI underlying these infectious diseases. We have already collected unique cohorts of patients with available WES or WGS data for all the infections we are studying, including > 800 patients with MSMD, >1500 with tuberculosis, >800 with viral encephalitis, and >10000 with COVID-19 related phenotypes. Although the patients are recruited worldwide, we have a majority of patients (>75%) of European origin. We will use cutting-edge approaches combining the extensive analysis of patient whole exome (WES) and whole genome (WGS) sequencing data with in-depth biochemical and immunological investigations. We have used and developed multiple methods for analyzing WES/WGS data and testing various genetic hypotheses. A majority of these methods are based on searching for an enrichment of rare variants in patients compared with appropriate controls. Therefore the possibility to use UK Biobank individuals as controls will strongly increase our power to detect those variants. In addition, we will pursue our development of methods to optimize the search of these variants. Along this line, we are also developing a new method to detect UPD with mosaicism that is probably largely underestimated among possible etiologies of human genetic disorders. For all these projects, it will be critical to estimate the prevalence of these UPD events in a very large general population such as the UK Biobank. The duration of the project is estimated to be 3 years. The discovery of novel IEI in infectious diseases has both major immunological and clinical implications. We have shown that the discovery of rare IEIs could act as a compass, via elucidation of the pathophysiology of disease in the patients, pointing to more common monogenic or autoimmune determinants of infectious diseases. The understanding of the genetic and immunological basis of infectious diseases thus obtained will also pave the way for the optimization of personalized prevention and treatment, with the development of novel therapeutic approaches for restoring immunity to infection. The project will also result in the production of reliable tools (software to detect UPD with or without mosaicism) that could be used by the researchers to improve the search for the genetic etiology of human diseases.1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 13226 | Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation | Jonathan Bohlen (+63) | 2024 | Journal of Clinical Investigation |
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