PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants
Open accessAbstract
Background Pathogenic variants of phospholipase C gamma 2 (PLCG2) cause 2 related forms of autosomal-dominant immune dysregulation (ID), PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID). Since describing these conditions, many PLCG2 variants of uncertain significance have been identified by clinical sequencing of patients with diverse features of ID. Objective We sought to functionally classify PLCG2 variants and explore known and novel genotype-function-phenotype relationships. Methods Clinical data from patients with PLCG2 variants were obtained via standardized questionnaire. PLCG2 variants were generated by mutagenesis of enhanced green fluorescent protein (EGFP)-PLCG2 plasmid, which was overexpressed in Plcg2-deficient DT-40 B cells. B-cell receptor-induced calcium flux and extracellular signal-regulated kinase phosphorylation were assayed by flow cytometry. In some cases, stimulation-induced calcium flux was also measured in primary patient cells. Results Three-fourths of PLCG2 variants produced functional alteration of B-cell activation, in vitro. Thirteen variants led to gain of function (GOF); however, most functional variants defined a new class of PLCG2 mutation, monoallelic loss of function (LOF). Susceptibility to infection and autoinflammation were common with both GOF and LOF variants, whereas a new phenotypic cluster consisting of humoral immune deficiency, autoinflammation, susceptibility to herpesvirus infection, and natural killer cell dysfunction was observed in association with multiple heterozygous LOF variants detected in both familial and sporadic cases. In some cases, PLCG2 variants produced greater effects in natural killer cells than in B cells. Conclusions This work expands the genotypic and phenotypic associations with functional variation in PLCG2, including a novel form of ID in carriers of heterozygous loss of PLCG2 function. It also demonstrates the need for more diverse assays for assessing the impact of PLCG2 variants on human disease.
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Many mutations discovered in PLCγ2 have been linked to the development of complex immune disorders as well as resistance to ibrutinib treatment in chronic lymphocytic leukaemia.
“Furthermore, many mutations discovered in PLCγ2 have been linked to the development of complex immune disorders as well as resistance to ibrutinib treatment in chronic lymphocytic leukaemia.”
From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Baysac et al., 2024
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Wu, X., Zhang, J., & Shen, M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1556372 · Cited by 1 · see citing works
Chou, S., Bailey, A. C., Baysac, K., Oler, A. J., Milner, J. D., & Ombrello, M. J. (2024) · medRxiv · doi:10.1101/2024.03.16.24304180
Self-citationTherapeutic Approaches for Periodic Fever Syndromes and Autoinflammatory Disorders
Guerra, A. A. H., & Dimitriades, V. R. (2025) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2025.01.006
Akoğlu, G., Yaz, İ., Esenboğa, S., Yılmaz, S., Mülazımoğlu, D. D., & Cağdaş, D. N. (2025) · Research Square · doi:10.21203/rs.3.rs-6201807/v1
Monogenic Autoinflammatory Diseases
Fournier, B., & Bader‐Meunier, B. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00166-6
Zhang, X., Liu, H., Tang, X., Hui, X., Shen, Y., Yang, H., Liu, J., Li, H., Zhou, C., & Zhao, S. (2025) · Pediatric Allergy and Immunology · doi:10.1111/pai.70138
Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune functionPreprint
Ma, M., Zheng, Y., Deng, M., Lu, S., Pan, X., Luo, X., Etoundi, M., Li‐Kroeger, D., Worley, K. C., Burrage, L. C., et al. (2025) · eLife · doi:10.7554/elife.95887.2
Defects in B Cell Survival and Activation
Akhoon, C., & Yong, P. F. K. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00196-4
The protective PLCG2 variants delay Alzheimer's disease onset age in APOE ϵ4 carriersPreprint
Jeskanen, H., Heikkinen, S., Kervinen, I., Lehtisalo, J., Ngandu, T., Willman, R.-M., Rosa, J., Hoffmann, D., FinnGen, Leinonen, V., et al. (2025) · medRxiv · doi:10.1101/2025.09.22.25336304
Early-onset bibasilar emphysema in a patient with PLCG2-related immune dysregulation
Sundlof, A., Nathan, J., Gerhard, G. S., & Salerno, D. A. (2025) · Respiratory Medicine Case Reports · doi:10.1016/j.rmcr.2025.102308
Overlap of familial Mediterranean fever and APLAID treated with anakinra: a case-based review
Akoğlu, G., Yaz, İ., Esenboğa, S., Yılmaz, S., Mülazımoğlu, D. D., & Cağdaş, D. N. (2025) · Clinical Rheumatology · doi:10.1007/s10067-025-07760-x
PLCG2 promotes cell survival and mitophagy of small cell lung cancer via regulating VCP
Jiang, J., Zhu, J., Xiao, Y., & Gan, L. (2025) · Anti-Cancer Drugs · doi:10.1097/cad.0000000000001770
Kang, Z., & Zhang, L. (2025) · Molecular and Cellular Pediatrics · doi:10.1186/s40348-025-00212-1
Di, H., Wang, Z., Ma, R., Yuan, X., Jiang, L., Zhou, P., Wang, L., & Zhu, Z. (2026) · Discover Oncology · doi:10.1007/s12672-026-04539-7
Gene Therapy and RNA-Based Innovations for Management of Alziemer's
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Inborn Errors of Immunity and Rheumatic Disease
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Self-citationPeriodic Fever Syndromes and Other Inherited Autoinflammatory Diseases
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Self-citationPhosphoinositide turnover through PLCγ regulates Draper-dependent engulfment in gliaPreprint
Storer, F., MacKinnon, E. A., Clarke, H., Maddison, D. C., Amadio, L., Susobhanan, T., Malik, B. R., Peters, O. M., & Smith, G. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.04.729572
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Chronic Urticaria-Associated Syndromes: Is Andersen–Tawil Syndrome One of Them?
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Self-citationRecent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases
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Immunogenetics underlying severe coccidioidomycosis
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The immune system in postnatal lung development
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Genetic Testing in Clinical Immunology: What to Know and How to Do It
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Self-citationGenetic and non-genetic drivers of immune dysregulation: Beyond autoinflammation and autoimmunity
Jamilloux, Y., Doutriaux, C., Lepage, M., Martel, N., & Henry, T. (2026) · Autoimmunity Reviews · doi:10.1016/j.autrev.2026.104202
- Authors
- Baysac, K., Sun, G., Nakano, H., Schmitz, E. G., Cruz, A. C., Fisher, C., Bailey, A. C., Abbott, J. K., Aldave Becerra, J. C., Allenspach, E. J., Assing, K., Atkinson, T. P., Bargir, U. A., Baxter, S. K., Bergerson, J. R. E., Bista, R., Blanche, S., Buckley, L. M., Butte, M., Carcamo, B., Chandrakala, S., Chen, K., Chervinskiy, S., Chinn, I. K., Chong, H. J., Coffey, K. E., Copland, A. P., Cowen, E. W., Cros, G., De Bruycker, J. J., Teresa de la Morena, M., Ehlayel, M., Forbes Satter, L. R., Gelfand, E. W., Gilliaux, O., Glover, S. C., Gorman, M., Griffin, T. A., Grimbacher, B., Gru, A. A., Haddad, E., Hadjadj, J., Hajjar, J., Hauck, F., Hautala, T., Holland, S. M., Hsieh, E. W. Y., Hsu, F. I., Jacquemin, E., Jindal, A. K., Kahn, S. A., Keller, M. D., Kobayashi, R. H., Krupski, C., Larkin, A., Lawrence, M. G., Madkaikar, M., Malphettes, M., Martelius, T., Mehta, M., Metcalfe, D. D., Meyts, I., Nannapaneni, N., Ocejo Vinyals, J. G., Olivier, K., Ombrello, A. K., Orange, J. S., Rabinovitch, N., Rauscher, C. K., Redfern, A., Reynolds, P. R., Rieux-Laucat, F., Secord, E., Seeborg, F. O., Seppänen, M. R. J., Sereti, I., Shin, D. S., Shin, J. J., Snapper, S. B., Suri, D., Tangcheewinsirikul, S., Thatayatikom, A., Torgerson, T., Touzot, F., Uzel, G., Varjosalo, M., Vasconcelos, D. F. P., von Bernuth, H., Walsh, T., Walter, J. E., Ward, B. R., Wittkowski, H., Wysocki, C. A., Mace, E., Milner, J. D., & Ombrello, M. J.
- Affiliations
- National Institutes of Health (US)
- Columbia University (US)
- Corresponding author
- Ombrello, Michael J.
- ORCID
- Sun, Guangping
- Schmitz, Elizabeth G.
- Cruz, Anthony C.
- Abbott, Jordan K.
- Allenspach, Eric J.
- Assing, Kristian
- Atkinson, T. Prescott
- Bargir, Umair A.
- Baxter, Sarah K.
- Bergerson, Jenna R.E.
- Bista, Ranjan
- Buckley, Lenore M.
- Butte, Manish
- Carcamo, Benjamin
- Chen, Karin
- Chervinskiy, Sheva
- Chinn, Ivan K.
- Chong, Hey J.
- Coffey, Kara E.
- Cowen, Edward W.
- Cros, Guilhem
- Ehlayel, Mohammed
- Gelfand, Erwin W.
- Gilliaux, Olivier
- Gorman, Mark
- Grimbacher, Bodo
- Gru, Alejandro A.
- Hajjar, Joud
- Hauck, Fabian
- Hautala, Timo
- Holland, Steven M.
- Hsieh, Elena W.Y.
- Hsu, Florence Ida
- Jacquemin, Emmanuel
- Jindal, Ankur Kumar
- Kahn, Stacy A.
- Keller, Michael D.
- Kobayashi, Roger H.
- Krupski, Christa
- Lawrence, Monica G.
- Madkaikar, Manisha
- Malphettes, Marion
- Martelius, Timi
- Mehta, Mehek
- Metcalfe, Dean D.
- Meyts, Isabelle
- Nannapaneni, Naveen
- Olivier, Kenneth
- Ombrello, Amanda K.
- Orange, Jordan S.
- Rabinovitch, Nathan
- Reynolds, Paul R.
- Secord, Elizabeth
- Seeborg, Filiz O.
- Seppänen, Mikko R.J.
- Sereti, Irini
- Shin, Daniel S.
- Shin, Junghee J.
- Snapper, Scott B.
- Suri, Deepti
- Tangcheewinsirikul, Sirikarn
- Thatayatikom, Akaluck
- Torgerson, Troy
- Touzot, Fabien
- Varjosalo, Markku
- Walsh, Thomas
- Walter, Jolan E.
- Ward, Brant R.
- Wittkowski, Helmut
- Wysocki, Christian A.
- Mace, Emily
- Milner, Joshua D.
- Ombrello, Michael J.
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2024-01
- Volume
- 153
- Issue
- 1
- Pages
- 230-242
- ISSN
- 0091-6749 (ISSN-L)
- PMC
- PMC11337301
- OpenAlex
- W4387063607
- Cited by
- 63
- References
- 44
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 12 · 2023: 1
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Allergy and Clinical Immunology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- PLCγ2, gain-of-function mutations, loss-of-function mutations, genotype-phenotype correlation, ERK1/2 phosphorylation, NK cell dysfunction, humoral immune deficiency, autoinflammation, antibody deficiency
- MeSH terms
- Autoimmune Diseases, Calcium, Humans, Immunologic Deficiency Syndromes, Mutation, Phospholipase C gamma
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