Somatic STAT5B^N642H mutations shape variable immune landscapes resulting in heterogenous immune diseases

Background: Inborn errors of immunity are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking inborn errors of immunity. While early postzygotic mosaicism is the predominant mechanism, genetic variants causing a selective advantage to hematopoietic progenitors and/or mature immune cells may cause immune dysregulation and initiate disease at any age. Somatic mosaicism for STAT5B^N642H was linked to severe allergic disease in infancy, but its full clinical spectrum and underlying mechanisms remain incompletely defined.<br><br>Objective: We elucidated how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function, and clinical phenotypes.<br><br>Methods: We investigated 3 new patients-including one adult-with STAT5B^N642H mosaicism using deep sequencing, flow and mass cytometry, and functional immune assays. Mutant cell distribution was mapped across blood lineages. A mouse model with mosaic STAT5B^N642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes.<br><br>Results: Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2-mediated proliferation, effector differentiation, and oligoclonal T-cell expansions. In mice, a few mutant hematopoietic stem cells reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T-cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients.<br><br>Conclusion: A single somatic variant in a few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.