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 a patient with IKZF1 haploinsufficiency, patients with lupus 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 the type I interferon (IFN) pathway was evaluated by measuring serum cytokine levels, IFN signatures, and the phosphorylation status of JAK and STAT. RESULTS: T cells. Pseudotime analysis in this patient suggested simplified B cell differentiation trajectories with arrested maturation and naive-like cell resurgence. Weighted gene coexpression network analysis identified a lupus-linked gene module (IKZF1, DUSP1, JUN, FOS), with inferred networks suggesting compensatory stress circuits (DUSP1, DDX17). Overactivation of the 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: 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.