Sarah Grün Sarah Grün Anne Rensing-Ehl Anne Rensing-Ehl Tobias Suske (University of Veterinary Medicine Vienna) Tobias Suske Julian Wolter-Mess Julian Wolter-Mess Jonathan Gehrig Jonathan Gehrig Jasmin Mann Jasmin Mann Christoph König Christoph König Mathias Hauri Mathias Hauri Maximilian Heeg Maximilian Heeg Timothy Ronan Leahy Timothy Ronan Leahy David Genevieve David Genevieve Jean-Baptiste Gaillard Jean-Baptiste Gaillard Martin Broly Martin Broly Arnaud Bourdin Arnaud Bourdin Carla Castro Carla Castro Lea Seidel Lea Seidel Bertram Bengsch Bertram Bengsch Peter Aichele Peter Aichele Kristoffer Weißert Kristoffer Weißert Juncal Fernandez-Orth Juncal Fernandez-Orth Vincent Schipperges Vincent Schipperges Geoffroy Andrieux Geoffroy Andrieux Melanie Boerries Melanie Boerries Nina Cabezas-Wallscheid Nina Cabezas-Wallscheid Miriam Erlacher Miriam Erlacher Roland Elling Roland Elling Carsten Speckmann Carsten Speckmann Lara Heller Lara Heller Björn Schulte Björn Schulte Myriam Lorenz Myriam Lorenz Klaus Schwarz Klaus Schwarz Richard Moriggl Richard Moriggl Stephan Ehl Stephan Ehl Elsevier 2026 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. PDFDocument eng 2026-08-25T08:12:15.540676576Z 2026 STAT5B somatic mosaicism hematopoietic stem cells clonal hematopoiesis immune dysregulation T-cell lymphoproliferation autoimmunity atopy mTOR inhibition 2740254 b application/pdf http://creativecommons.org/licenses/by/4.0/