Unraveling primary immune regulatory disorders: A comprehensive narrative review from clinical suspicion to diagnosis and management

Historically defined by infectious susceptibility, Primary Immunodeficiencies (PIDs) have evolved into Inborn Errors of Immunity (IEI), including Primary Immune Regulatory Disorders (PIRDs), where immune dysregulation predominates. Despite genetic advances, a 70% "diagnostic gap" persists. This review provides a framework for PIRD management through phenotypic selection, deep sequencing for mosaicism, and multi-omics integration. Phenotypic stringency, such as that applied to fulfill ALPS or IPEX-like criteria, can improve diagnostic yield. Technologies like long-read genome sequencing (lrGS) and targeted amplicon-based deep sequencing (ADS) are essential for resolving structural variants and low frequency variant allele fraction (VAF) somatic events (VAF < 5%) missed by standard pipelines. Furthermore, precision therapies, including JAK inhibitors, Leniolisib, and Abatacept, seems promissing therapeutic approaches to restore immunological homeostasis. Closing the diagnostic gap requires a multimodal approach integrating clinical expertise, advanced genomics, and functional translation. Ultimately, precision immunology is shifting IEI management toward targeted control and potential cure via gene editing.