<scp>UNC13D</scp> 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.