Deficiency of NBAS causes immune dysregulation due to hyperactivation of IFN signaling

NBAS deficiency is a multisystem disorder, but its immunologic manifestations and underlying mechanisms remain poorly defined. Here, we expand the genotypic and phenotypic spectrum of NBAS deficiency through four patients carrying five loss-of-function NBAS mutations. Minigene assays and RNA analysis showed that these splicing or missense mutations resulted in aberrant alternative splicing. Clinically, the patients showed early-onset recurrent or persistent cytopenias and immune dysregulation, together with severe infections, inflammatory activation, and multi-organ involvement, including renal and neurologic manifestations. Transcriptomic analysis revealed overactivation of type I interferon signaling pathways compared with healthy controls, and single-cell RNA sequencing demonstrated that this upregulated inflammation was predominantly driven by myeloid cells. Together, these findings identify NBAS deficiency as a cause of immune dysregulation characterized by myeloid-driven type I interferonopathy, expand the clinical spectrum of NBAS-related disorders, and highlight the critical role of NBAS in maintaining immune homeostasis.