Since 1952, the majority of primary immunodeficiencies identified have been linked to loss-of-function abnormalities. Many gain-of-function mutations causing immunodeficiency have been found since the introduction and widespread use of unbiased next-generation sequencing diagnostic methods, followed by functional validation techniques. This review focuses on novel pathophysiological mechanisms and treatment methods for primary immunodeficiencies caused by gain-of-function mutations. The most recent discoveries in gain-of-function primary immunodeficiencies were reviewed, with a focus on increased infection susceptibility but also immunological dysregulation and autoimmunity. Updates on pathophysiology mechanisms, different mutation types, clinical features, laboratory markers, current and potential new treatments for patients with caspase recruitment domain family member 11, signal transducer and activator of transcription 3, phosphatidylinositol-4,5-biphosphate 3-kinase catalytic 110, phosphatidylinositol-4,5-biphosphate 3-kinase catalytic 110, phosphatidylinositol-4,5-biphosphate 3-kinase regulatory subunit 1 were reviewed.

With the discovery of gain-of-function mutations as a cause of immunodeficiency, novel genetic pathophysiological mechanisms and new-targeted therapeutic methods as potential rescue therapies for these illnesses have been revealed.