Demystifying Genetic Workup of Inborn Errors of Immunity

Genetically driven immune diseases (GIDs) are germline or somatic errors of immunity, representing an expanding and diagnostically complex group of genetic disorders. While genomic advances have enhanced their detection, interpretation of genetic data remains a major challenge due to significant genotypic and phenotypic heterogeneity, incomplete knowledge about genotype-phenotype connections, and the diverse layers of mechanisms contributing to each patient's specific expression of disease. In this review, we propose a clinically oriented framework for the genetic evaluation of patients with suspected GIDs.

Using disorders featuring predominantly adaptive immune dysregulation as representative examples - hypomorphic defects in lymphocyte development (RAG1, RAG2), defects of central tolerance (AIRE), defects of peripheral tolerance (FOXP3), cytokine-mediated immune regulation (IL2RA, IL2RB), activation-induced cell death (FAS), and canonical NF-κB signaling (CARD11 gain-of-function) - we provide a practical approach to the selection and use of clinically available genetic tests, emphasizing context-dependent strategies based on each patient's clinical and immune findings. We also highlight key limitations of current genetic testing and emerging approaches aimed at improving diagnostic yield. This review provides a practical, stepwise, mechanism-informed framework for the genetic evaluation of patients with suspected GIDs that integrates clinical phenotyping with immune and genetic data. By emphasizing appropriate test selection, recognition of diagnostic limitations, and the use of complementary approaches in unresolved cases, this framework aims to support accurate molecular diagnosis and personalized management of patients with immune dysregulation.