Somatic STAT5BN642H mutations shape variable immune landscapes resulting in heterogenous immune diseases

December 24, 2025

Sarah Grün 1, Anne Rensing-Ehl 2, Tobias Suske 3, Julian Wolter-Mess 4, Jonathan Gehrig 5, Jasmin Mann 5, Christoph König 5, Mathias Hauri 6, Maximilian Heeg 7, Timothy Ronan Leahy 8, David Genevieve 9, Jean-Baptiste Gaillard 10, Martin Broly 11, Arnaud Bourdin 12, Carla Castro 13, Lea Seidel 14, Bertram Bengsch 15, Peter Aichele 13, Kristoffer Weißert 13, Juncal Fernandez-Orth 16, Vincent Schipperges 17, Geoffroy Andrieux 17, Melanie Boerries 18, Nina Cabezas-Wallscheid 19, Miriam Erlacher 20, Roland Elling 21, Carsten Speckmann 7, Lara Heller 22, Björn Schulte 22, Myriam Lorenz 23, Klaus Schwarz 24, Richard Moriggl 25, Stephan Ehl 26

Abstract

Background: Inborn errors of immunity (IEI) are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking IEI. 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: To elucidate how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function and clinical phenotypes.

Methods: We investigated three 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 HSCs 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: Our findings illuminate how a single somatic variant in few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.

Keywords: Atopy; Autoimmunity; Clonal hematopoiesis; Hematopoietic stem cells; Immune dysregulation; STAT5B; Somatic mosaicism; T cell lymphoproliferation; mTOR inhibition.

  1. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Signalling Research Centre CIBSS, University of Freiburg, Freiburg, Germany.
  2. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: stephan.ehl@uniklinik-freiburg.de.
  3. Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
  4. Faculty of Biology, University of Freiburg, Freiburg, Germany; Signalling Research Centre CIBSS, University of Freiburg, Freiburg, Germany; Max-Planck-Institute for Immunobiology and Epigenetics, Freiburg, Germany.
  5. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  6. Division of Stem Cell Transplantation, University Children’s Hospital Zurich – Eleonore Foundation & Children’s Research Center (CRC), Zurich, Switzerland.
  7. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  8. Children’s Health Ireland at Crumlin and University of Dublin, Trinity College Dublin, Dublin, Ireland.
  9. Montpellier University, INSERM U1183, IRMB, IHU Immu4Cure, Clinical Genetic Department, Montpellier University Hospital, Montpellier, France.
  10. Department of Molecular Genetics and Cytogenomics, University Hospital of Montpellier, Montpellier, France.
  11. Montpellier University, INSERM U1183, IRMB, IHU Immun4Cure, French National Reference Center of Autoinflammatory Diseases and Amyloidosis (CeRéMAIA), CHU Montpellier, Department of Molecular Genetics and Cytogenomics, National Reference laboratory of Autoinflammatory diseases, Montpellier, France.
  12. University of Montpellier, Department of Respiratory Disease, PhyMedExp, INSERM U1046, CNRS UMR 9214, CHU Montpellier, Montpellier, France.
  13. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  14. Faculty of Biology, University of Freiburg, Freiburg, Germany; Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  15. Signalling Research Centre CIBSS, University of Freiburg, Freiburg, Germany; Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  16. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  17. Institute of Medical Bioinfomatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  18. Institute of Medical Bioinfomatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between DKFZ and Medical Center – University of Freiburg.
  19. Signalling Research Centre CIBSS, University of Freiburg, Freiburg, Germany; Max-Planck-Institute for Immunobiology and Epigenetics, Freiburg, Germany.
  20. Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
  21. Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  22. Center of Human Genetics Tuebingen, Tuebingen, Germany; CeGaT GmbH Tuebingen, Tuebingen, Germany.
  23. Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
  24. Institute for Transfusion Medicine, University of Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wurttemberg – Hessen, Ulm, Germany.
  25. Department of Biosciences & Medical Biology, Paris Lodron University Salzburg, Salzburg, Austria.
  26. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centre CIBSS, University of Freiburg, Freiburg, Germany. Electronic address: stephan.ehl@uniklinik-freiburg.de.