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

April 01, 2026

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 2, Lea Seidel 13, Bertram Bengsch 14, Peter Aichele 2, Kristoffer Weißert 2, Juncal Fernandez-Orth 15, Vincent Schipperges 16, Geoffroy Andrieux 16, Melanie Boerries 17, Nina Cabezas-Wallscheid 18, Miriam Erlacher 19, Roland Elling 20, Carsten Speckmann 7, Lara Heller 21, Björn Schulte 21, Myriam Lorenz 22, Klaus Schwarz 23, Richard Moriggl 24, Stephan Ehl 25

Abstract

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.

Keywords: STAT5B; T-cell lymphoproliferation; atopy; autoimmunity; clonal hematopoiesis; hematopoietic stem cells; immune dysregulation; mTOR inhibition; somatic mosaicism.

  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.
  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. University of Montpellier, 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. 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.
  14. 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.
  15. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  16. Institute of Medical Bioinfomatics and Systems Medicine, 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; German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between DKFZ and Medical Center-University of Freiburg, Freiburg, Germany.
  18. Signalling Research Centre CIBSS, University of Freiburg, Freiburg, Germany; Max-Planck-Institute for Immunobiology and Epigenetics, Freiburg, Germany.
  19. 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.
  20. Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  21. Center of Human Genetics Tübingen, Tübingen, Germany; CeGaT GmbH Tübingen, Tübingen, Germany.
  22. Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
  23. 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.
  24. Department of Biosciences & Medical Biology, Paris Lodron University Salzburg, Salzburg, Austria.
  25. 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.