Somatic STAT5BN642H 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 STAT5BN642H was linked to severe allergic disease in infancy, but its full clinical spectrum and underlying mechanisms remain incompletely defined. Objective We elucidated how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function, and clinical phenotypes. Methods We investigated 3 new patients—including one adult—with STAT5BN642H 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 STAT5BN642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes. 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. Conclusion A single somatic variant in a few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease. Text Wissenschaftlicher Artikel Open Access eng http://creativecommons.org/licenses/by/4.0/ application/pdf STAT5B somatic mosaicism hematopoietic stem cells clonal hematopoiesis immune dysregulation T-cell lymphoproliferation autoimmunity atopy mTOR inhibition Sarah Grün Anne Rensing-Ehl Tobias Suske (University of Veterinary Medicine Vienna) Julian Wolter-Mess Jonathan Gehrig Jasmin Mann Christoph König Mathias Hauri Maximilian Heeg Timothy Ronan Leahy David Genevieve Jean-Baptiste Gaillard Martin Broly Arnaud Bourdin Carla Castro Lea Seidel Bertram Bengsch Peter Aichele Kristoffer Weißert Juncal Fernandez-Orth Vincent Schipperges Geoffroy Andrieux Melanie Boerries Nina Cabezas-Wallscheid Miriam Erlacher Roland Elling Carsten Speckmann Lara Heller Björn Schulte Myriam Lorenz Klaus Schwarz Richard Moriggl Stephan Ehl Elsevier Documento PDF Articolo scientifico doi:10.1016/j.jaci.2025.12.993 Journal of Allergy and Clinical Immunology Text journal article © 2025 The Authors open access 2026 https://phaidra.vetmeduni.ac.at/o:5455