Immune dysregulatory disorders: perspective from solving a diagnostic odyssey

Inborn errors of immunity (IEIs), once considered rare disorders characterized primarily by recurrent infections, are now recognized as a rapidly expanding group of diseases encompassing autoimmunity, autoinflammation, allergy, malignancy, and immune dysregulation. Advances in next-generation sequencing, functional immunology, and systems biology have revealed overlap between traditionally distinct disease categories and highlighted the complexity of genotype-phenotype relationships.

While this evolution has led to the discovery of hundreds of previously unrecognized disorders, it has also challenged conventional diagnostic paradigms and demonstrated how patients may have care spread across multiple specialties, without a clear medical home. These discoveries have also highlighted ongoing challenges translating scientific findings to the clinic including difficulties in accessing genomic testing, interpretation of variants of uncertain significance, impacts of incomplete penetrance and somatic mosaicism, and limited availability of specialized functional assays. Emerging computational approaches, including artificial intelligence, offer opportunities to accelerate diagnosis but cannot replace comprehensive clinical evaluation or longitudinal physician-patient relationships.

This perspective examines how the diagnostic odyssey for immune dysregulatory disorders has evolved, side-by-side with the changing framework for diagnosing rare immune diseases. We propose an integrated approach combining clinical phenotyping, genomics, functional validation, and multidisciplinary expertise to unite ongoing discovery between clinicians and scientists, diagnostics, and patient outcomes.