Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation

International audienceThe PI3K-AKT-mTOR signaling axis is a critical molecular pathway in humans, regulating multiple cellular processes. Phosphatidylinositol-3-kinases (PI3K) represent key signaling hubs for signal propagation, driving cell activation, cell polarization and morphological adaptations. Studies on PI3K in human disease have highlighted PI3K-gamma (PI3Kγ) as an appealing drug target for treatment of human disorders.2 Murine PI3Kγ studies showed its importance in regulating innate immune functions and development and activation of T cells, revealing its role in controlling inflammation. However, its role in the human immune system and diseases remains to be investigated

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity

Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies–defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities