Purpose and Overview

Inborn errors of immunity (IEI) are a growing group of monogenic disorders that extend well beyond the classical picture of recurrent infection, frequently presenting with autoimmunity, autoinflammation, allergy, or lymphoproliferation. Because a single gene can produce markedly different clinical phenotypes depending on how much protein expression and function a given variant preserves, genotype alone is often insufficient to explain or predict disease. This lecture reviews the clinical and molecular heterogeneity of IEI and outlines a practical diagnostic framework that integrates clinical presentation and family history, immune laboratory evaluation, and genetic analysis. Using illustrative patient cases, the session demonstrates how variants of uncertain significance are functionally validated to establish causality, and how an accurate mechanistic diagnosis shortens the diagnostic odyssey and informs pathway-specific therapy.