Single‐cell RNA sequencing informs precision targeting of monogenic lupus associated with IKZF1 haploinsufficiency

Objective This study aimed to investigate the mechanisms of immune dysregulation in a pediatric patient with monogenic lupus driven by IKZF1 ‐haploinsufficiency. Methods Peripheral immune cells from patient with IKZF1 ‐haploinsufficiency, lupus cases with no currently known genetic mutations, and healthy controls were analyzed using single‐cell RNA sequencing. Bioinformatic analyses, including pseudotime trajectory and network reconstruction were performed. Activation of type I interferon (IFN) pathway was evaluated by measuring serum cytokine levels, IFN signatures, and the phosphorylation status of Janus kinase (JAK) and signal transducer and activator of transcription (STAT). Results The patient with IKZF1 ‐haploinsufficiency exhibited notable B cell and T cell dysregulation, with nearly total absence of regulatory B cells (Bregs) and increased percentage of naive CD4 + T cells. Pseudotime analysis in this patient suggested simplified B cell differentiation trajectories with arrested maturation and naïve‐like cell resurgence. WGCNA identified a lupus‐linked gene module ( IKZF1, DUSP1, JUN, FOS ), with inferred networks suggesting compensatory stress circuits ( DUSP1, DDX17 ). Over‐activation of IFN‐JAK‐STAT signaling pathway was observed in the patient with IKZF1 ‐haploinsufficiency. Given persistent thrombocytopenia, baricitinib combined with mycophenolate mofetil was administered based on these findings. Her platelet count returned to normal in a month after combination therapy with baricitinib. Conclusion IKZF1 haploinsufficiency disrupted lymphocyte homeostasis, especially Bregs and naive CD4 + T cells, highlighting these as key IKZF1 ‐functional targets. A phenotype‐ and single‐cell‐based approach may offer a pathway toward more precise diagnosis and personalized treatment strategies for monogenic lupus. image