Targeted deep sequencing identifies mosaicism in patients with immune dysregulation - 05/05/26

Doi : 10.1016/j.jaci.2026.01.023

Elizabeth G. Schmitz, BS ^a, Alexander J. Paul, MS ^a, Rajarshi Ghosh, PhD ^b, Nermina Saucier, MS ^a, Ana Kolicheski, PhD ^a, Samuel I. Risma, BA ^a, Kristen P. McDaniels, BS ^a, Michelle Liu ^a, Katie L. Lewis, ScM ^b, Adriana A. de Jesus, MD, PhD ^c, Sara Alehashemi, MD, MPH ^c, Catrina C. Fronick, BS ^d, David Stein, PhD ^e,^f,^g, Daniela Dominguez, MD, MSc ^h, Linda T. Hiraki, MD, ScD ⁱ, Jessica H. Lee, CCRP ^j, Stephanie Norman, MPH ^k, Christine R. Peng, BSN, BS, RN ^k, Brant R. Ward, MD, PhD ^l, Leah H. Pettiford, FNP ^l, Anna Platt, MS, LCGC ^m, Monica G. Lawrence, MD ⁿ, Joseph M. Rocco, MD ^o, Waleed AL-Herz, MD ^p, Christa S. Zerbe, MD, MS ^c, T. Prescott Atkinson, MD, PhD ^q, Xiao P. Peng, MD, PhD ^r,^s, Eric J. Allenspach, MD, PhD ^t,^u, David P. Hoytema van Konijnenburg, MD, PhD ^v, Craig D. Platt, MD, PhD ^v, Megan Elkins, MHS ^v, Jolan E. Walter, MD, PhD ^w,^x, Jack J. Bleesing, MD, PhD ^y,^z, Amy Klion, MD ^aa, Ramya Ramaswami, MBBS, MPH ^ab, Gulbu Uzel, MD ^c, Michail S. Lionakis, MD, ScD ^c, Dilan Dissanayake, MD, PhD, FRCPC ^h, Helen C. Su, MD, PhD ^c, Irene Cortese, MD ^ac, Ivan J. Fuss, MD ^c, Jenna R.E. Bergerson, MD, MPH ^c, Lesia Dropulic, MD ^ad, Irini Sereti, MD, PhD ^o, Andrea Lisco, MD, PhD ^o, Yuval Itan, PhD ^f,^g,^ae,^af, Joshua D. Milner, MD ^ag,^ah, Dusan Bogunovic, PhD ^ag,^ah,^ai, Raphaela Goldbach-Mansky, MD, MHS ^c, V. Koneti Rao, MD ^c, Ottavia M. Delmonte, MD, PhD ^c, Luigi D. Notarangelo, MD ^c, Michael D. Keller, MD ^l, Jessica Durkee-Shock, MD, MHSc ^aj, Jeffrey I. Cohen, MD ^aj, Morgan N. Similuk, ScM ^b, Steven M. Holland, MD ^c, Malachi Griffith, PhD ^ak, Obi L. Griffith, PhD ^ak, Tiphanie P. Vogel, MD, PhD ^al, Scott Canna, MD ^j, Alexandra F. Freeman, MD ^c, Magdalena A. Walkiewicz, PhD ^b, Megan A. Cooper, MD, PhD ^a,^⁎

^a Department of Pediatrics, Division of Rheumatology/Immunology, Washington University in St Louis, St Louis, Mo

^b Centralized Sequencing Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Md

^c Laboratory of Clinical Immunology and Microbiology, NIAID, Bethesda, Md

^d McDonnell Genome Institute at Washington University School of Medicine, St Louis, Mo

^e Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY

^f The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

^g Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY

^h Division of Rheumatology, Departments of Paediatrics and Immunology, Cell and Systems Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada

ⁱ Division of Rheumatology, Genetics & Genome Biology, Research Insittute, The Hospital for Sick Children, Toronto, Ontario, Canada

^j Immune Dysregulation Program, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa

^k Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC

^l Division of Allergy and Immunology, Children’s National Hospital, Washington, DC

^m University of Virginia School of Medicine, Department of Pediatrics, Division of Pediatric Genetics, Charlottesville, Va

ⁿ University of Virginia School of Medicine, Department of Medicine, Division of Asthma allergy and Immunology, Charlottesville, Va

^o Laboratory of Immunoregulation, NIAID, Bethesda, Md

^p Department of Pediatrics, College of Medicine, Kuwait University, Kuwait City, Kuwait

^q Department of Pediatrics, Division of Allergy and Immunology, University of Alabama at Birmingham, Birmingham, Ala

^r New York Center for Rare Diseases; Division of Pediatric Genetic Medicine, Department of Pediatrics, The Children’s Hospital at Montefiore, Bronx, NY

^s Division of Genomics, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY

^t Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, Wash

^u Department of Pediatrics, University of Washington, Seattle, Wash

^v Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, Mass

^w Division of Allergy and Immunology, Departments of Pediatrics and Medicine, University of South Florida Morsani College of Medicine, Tampa, Fla

^x Division of Allergy and Immunology, Department of Medicine, Johns Hopkins All Children’s Hospital, St Petersburg, Fla

^y Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

^z Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

^aa Laboratory of Parasitic Diseases, NIAID, Bethesda, Md

^ab HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md

^ac Experimental Immunotherapeutics Unit, National Institute of Neurological Disorders and Stroke, Bethesda, Md

^ad Vaccine Research Center, NIAID, Bethesda, Md

^ae The Windreich Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY

^af Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY

^ag Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY

^ah Division of Pediatric Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University, New York, NY

^ai Columbia Center for Genetic Errors of Immunity, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY

^aj Laboratory of Infectious Diseases, NIAID, Bethesda, Md

^ak Department of Medicine, Division of Oncology, Washington University in St Louis, St Louis, Mo

^al Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children’s Hospital, Houston, Tex

^∗ Corresponding author: Megan A. Cooper, MD, PhD, 660 S Euclid Ave, Box 8208, St Louis, MO 63110. 660 S Euclid Ave Box 8208 St Louis MO 63110

Abstract

Background

Identifying 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.

Objective

We used a discovery-based approach to identify mosaic variants in genes relevant to immune dysregulation in patient and healthy cohorts.

Methods

We 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.

Results

We 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.

Conclusion

These 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.

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Key words : Inborn errors of immunity, genetic errors of immunity, primary immunodeficiency, genetic sequencing, mosaicism, somatic mutation, autoimmune lymphoproliferative syndrome

Abbreviations used : ALPS, ALPS-sFAS, CAPS, ddPCR, DNT, EBV, FAS, GEI, gnomAD, GOF, IEI, JAK, LMP, LOF, MP, NK, NLRP3, NRAS, PBMC, SAMD9L, STAT3, TLR, TNFAIP3, UBA1, UMS, V1, V2, VAF, VEXAS

Plan

Methods

Patients and DNA samples

Deep sequencing and mosaic variant detection

Results

Patient characteristics

Targeted deep sequencing, identification, and validation of mosaic variants

Identification of mosaic variants in healthy and affected individuals

Potential pathogenicity of mosaic variants

Scoring potential pathogenicity of variants

Immune cell populations in mosaic variants

Discussion

The first 2 authors contributed equally to this article, and both should be considered first author.

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Vol 157 - N° 5

P. 1179-1194 - mai 2026 Retour au numéro

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Clinical relevance of mosaic variants detected by exome sequencing
Rajarshi Ghosh, Zeeshan Fazal, Andrew J. Oler, Mari J. Tokita, Katie L. Lewis, Alexander J. Paul, Elizabeth G. Schmitz, Nermina Saucier, Jia Yan, Michael Kamen, Bryce A. Seifert, NIAID Centralized Sequencing Program,, Amy D. Klion, Paneez Khoury, Ottavia M. Delmonte, Luigi D. Notarangelo, Alexandra F. Freeman, Christa S. Zerbe, Gulbu Uzel, Dean D. Metcalfe, Hirsh D. Komarow, Melody C. Carter, David H. McDermott, Philip M. Murphy, Kenneth N. Olivier, Ivan Fuss, Warren Strober, V. Koneti Rao, Jenna R.E. Bergerson, Adriana Almeida de Jesus, Raphaela Goldbach-Mansky, Waleed Al-Herz, Steven M. Holland, Megan A. Cooper, Morgan N. Similuk, Magdalena A. Walkiewicz, Adrienne Borges, Nicole Gentile, Ekaterina E. Damskey, Sruthi Srinivasan, Rachel G. Moses, Nadjalisse C. Reynolds-Lallement, Sarah Bannon, Aislinn Bloom

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Targeted deep sequencing identifies mosaicism in patients with immune dysregulation - 05/05/26

Abstract

Background

Objective

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Results

Conclusion

Plan

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