UNC13D in Familial Hemophagocytic Lymphohistiocytosis and Beyond: Functional Mechanisms, Genetic Variants, Multisystem Disease Spectrum and Clinical Implications

The UNC13D gene encodes Munc13‐4, a key regulator of cytotoxic granule exocytosis in effector immune cells, enabling the release of perforin and granzymes that are essential for cytotoxic function and immune surveillance. Loss‐of‐function mutations in UNC13D result in immune dysregulation syndromes, most notably familial hemophagocytic lymphohistiocytosis (fHLH, also referred to as FHL). This review provides a comprehensive overview of UNC13D, including its structural characteristics, biological functions, and spectrum of pathogenic variants. We summarize the mechanistic roles of Munc13‐4 in granule‐mediated cytotoxicity and examine the clinical correlations between UNC13D mutations and fHLH type 3 (FHL3). Furthermore, we discuss emerging evidence linking UNC13D dysfunction to a broader range of diseases, highlighting its clinical relevance and potential as both a diagnostic biomarker and therapeutic target. Overall, this review aims to bridge the gap between molecular mechanisms and clinical translation in UNC13D‐related disorders.