ArticleThe Journal of allergy and clinical immunology2026
Targeted deep sequencing identifies mosaicism in patients with immune dysregulation.
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Article in The Journal of allergy and clinical immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Advancements in Diagnosis and Care for Immune Dysregulation and Inborn Errors of Immunity in Pediatric Rheumatology: Our 50-Year Journey.Arthritis care & research · 2026Review
- Somatic Variants in Immune Dysregulation: An Ongoing Challenge.Arthritis & rheumatology (Hoboken, N.J.) · 2026Article
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Authors and funding
64 authors.
Elizabeth G SchmitzDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
Alexander J PaulDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
Rajarshi GhoshCentralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md.
Nermina SaucierDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
Ana KolicheskiDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
Samuel I RismaDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
Kristen P McDanielsDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
Michelle LiuDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo.
Katie L LewisCentralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md.
Adriana A de JesusLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Sara AlehashemiLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Catrina C FronickMcDonnell Genome Institute at Washington University School of Medicine, St Louis, Mo.
David SteinDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
Daniela DominguezDivision of Rheumatology, Departments of Paediatrics and Immunology, Cell and Systems Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
Linda T HirakiDivision of Rheumatology, Genetics & Genome Biology, Research Insittute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jessica H LeeImmune Dysregulation Program, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
Stephanie NormanCenter for Cancer and Immunology Research, Children's National Hospital, Washington, DC.
Christine R PengCenter for Cancer and Immunology Research, Children's National Hospital, Washington, DC.
Brant R WardDivision of Allergy and Immunology, Children's National Hospital, Washington, DC.
Leah H PettifordDivision of Allergy and Immunology, Children's National Hospital, Washington, DC.
Anna PlattUniversity of Virginia School of Medicine, Department of Pediatrics, Division of Pediatric Genetics, Charlottesville, Va.
Monica G LawrenceUniversity of Virginia School of Medicine, Department of Medicine, Division of Asthma allergy and Immunology, Charlottesville, Va.
Joseph M RoccoLaboratory of Immunoregulation, NIAID, Bethesda, Md.
Waleed Al-HerzDepartment of Pediatrics, College of Medicine, Kuwait University, Kuwait City, Kuwait.
Christa S ZerbeLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
T Prescott AtkinsonDepartment of Pediatrics, Division of Allergy and Immunology, University of Alabama at Birmingham, Birmingham, Ala.
Xiao P PengNew York Center for Rare Diseases; Division of Pediatric Genetic Medicine, Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, NY; Division of Genomics, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY.
Eric J AllenspachCenter for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash; Department of Pediatrics, University of Washington, Seattle, Wash.
David P Hoytema van KonijnenburgDivision of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Craig D PlattDivision of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Megan ElkinsDivision of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Jolan E WalterDivision of Allergy and Immunology, Departments of Pediatrics and Medicine, University of South Florida Morsani College of Medicine, Tampa, Fla; Division of Allergy and Immunology, Department of Medicine, Johns Hopkins All Children's Hospital, St Petersburg, Fla.
Jack J BleesingDivision of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Amy KlionLaboratory of Parasitic Diseases, NIAID, Bethesda, Md.
Ramya RamaswamiHIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md.
Gulbu UzelLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Michail S LionakisLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Dilan DissanayakeDivision of Rheumatology, Departments of Paediatrics and Immunology, Cell and Systems Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
Helen C SuLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Irene CorteseExperimental Immunotherapeutics Unit, National Institute of Neurological Disorders and Stroke, Bethesda, Md.
Ivan J FussLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Jenna R E BergersonLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Lesia DropulicVaccine Research Center, NIAID, Bethesda, Md.
Irini SeretiLaboratory of Immunoregulation, NIAID, Bethesda, Md.
Andrea LiscoLaboratory of Immunoregulation, NIAID, Bethesda, Md.
Yuval ItanThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; The Windreich Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Joshua D MilnerDepartment of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Division of Pediatric Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University, New York, NY.
Dusan BogunovicDepartment of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Division of Pediatric Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University, New York, NY; Columbia Center for Genetic Errors of Immunity, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY.
Raphaela Goldbach-ManskyLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
V Koneti RaoLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Ottavia M DelmonteLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Luigi D NotarangeloLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Michael D KellerDivision of Allergy and Immunology, Children's National Hospital, Washington, DC.
Jessica Durkee-ShockLaboratory of Infectious Diseases, NIAID, Bethesda, Md.
Jeffrey I CohenLaboratory of Infectious Diseases, NIAID, Bethesda, Md.
Morgan N SimilukCentralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md.
Steven M HollandLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Malachi GriffithDepartment of Medicine, Division of Oncology, Washington University in St Louis, St Louis, Mo.
Obi L GriffithDepartment of Medicine, Division of Oncology, Washington University in St Louis, St Louis, Mo.
Tiphanie P VogelDivision of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex.
Scott CannaImmune Dysregulation Program, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
Alexandra F FreemanLaboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md.
Magdalena A WalkiewiczCentralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md.
Megan A CooperDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo. Electronic address: Cooper_m@wustl.edu.
Funding
Washington University Center for Cellular ImagingP30CA091842 · NCI · WASHINGTON UNIVERSITY · PI TIMOTHY J. EBERLEIN · 2001 to 2026
$128.0MCentral Sequencing InitiativeZICAI001244 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI HOLLAND, STEVEN · 2019 to 2025
$24.0MDefining New Human Immunodeficiency and Immunodysregulation DisordersZIAAI001059 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI SU, HELEN CHUN-HUI · 2009 to 2025
$20.5MCharacterization of the cellular and molecular bases of inborn errors of immunityZIAAI001222 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI NOTARANGELO, LUIGI · 2017 to 2025
$15.2MTRAINING PROGRAM IN IMMUNOLOGY AND IMMUNOGENETICST32AI007163 · NIAID · WASHINGTON UNIVERSITY · PI Kenneth M Murphy, Kodi S Ravichandran · 1985 to 2026
$14.8MThe Child Heath Research CenterK12HD052896 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI Wendy K Chung · 2007 to 2026
$7.9MSomatic variants as drivers of genetic errors of immunityP01AI186771 · NIAID · WASHINGTON UNIVERSITY · PI Joshua D. Milner · 2025 to 2026
$7.5MHuman ISG15 and USP18 Deficiencies Underlying Type I InterferonopathiesR01AI127372 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Dusan Bogunovic · 2017 to 2026
$4.7MStandardized and Genome-Wide Clinical Interpretation of Complex Genotypes for Cancer Precision MedicineU24CA237719 · NCI · WASHINGTON UNIVERSITY · PI GRIFFITH, OBI L. · 2019 to 2023
$3.8MImmunologic and Predictive Features of MIS-CR01HD108467 · NICHD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Dusan Bogunovic · 2022 to 2026
$2.7MText Mining and Large Language Models for AI-Driven Evidence-Based Functional Annotation of Clinical VariantsU24CA275783 · NCI · WASHINGTON UNIVERSITY · PI Malachi Griffith, Obi L. Griffith · 2023 to 2026
$2.6MInborn Errors of Immunity Leading to Autoinflammatory SyndromesR01AI148963 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI BOGUNOVIC, DUSAN · 2020 to 2024
$2.5MIntramural NIH HHS ZIA AI001059Intramural NIH HHS ZIA AI001222Intramural NIH HHS ZIC AI001244NCI NIH HHS P30 CA091842NCI NIH HHS U24 CA237719NCI NIH HHS U24 CA258115NCI NIH HHS U24 CA275783NIAID NIH HHS P01 AI186771NIAID NIH HHS R01 AI127372NIAID NIH HHS R01 AI148963NIAID NIH HHS R21 AI168957NIAID NIH HHS T32 AI007163NICHD NIH HHS K12 HD052896NICHD NIH HHS R01 HD108467
Abstract
backgroundIdentifying genetic mechanisms of inborn errors of immunity (IEI) is important for diagnosis and treatment of patients, yet most patients with suspected IEI have negative genetic testing results. Genetic mosaicism is an emerging mechanism of IEI, but it is challenging to identify.
objectiveWe used a discovery-based approach to identify mosaic variants in genes relevant to immune dysregulation in patient and healthy cohorts.
methodsWe developed custom panels for high-depth sequencing of genes known or hypothesized to cause dominant immune dysregulation. Samples from 452 patients with immune dysregulation (affected) and 154 currently healthy were sequenced using 71- or 101-gene targeted panels.
resultsWe identified mosaic variants in 9.5% of undiagnosed patients and 7.8% of healthy individuals. Using a strategy to predict pathogenicity of variants in IEI, 33% of variants identified in patients were predicted to be likely pathogenic or pathogenic, while no mosaic variants in healthy individuals were predicted to be pathogenic. Genes with mosaicism in >1 affected undiagnosed patients included FAS, STAT3, CARD11, CARD14, NRAS, TNFAIP3, NLRP3, and IKZF2. Four patients had variants in FAS with allele fractions <5% in blood but highly enriched in double-negative T cells, diagnostic for somatic FAS autoimmune lymphoproliferative syndrome.
conclusionThese findings establish the utility of a high-depth sequencing panel to identify mosaic variants and demonstrate that mosaicism in immune-relevant genes is present in healthy individuals.
Indexed as
Immune System DiseasesMosaicismFemaleHigh-Throughput Nucleotide SequencingHumansMaleautoimmune lymphoproliferative syndromegenetic errors of immunitygenetic sequencingInborn errors of immunitymosaicismprimary immunodeficiencysomatic mutation
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