PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants - 04/01/24

Doi : 10.1016/j.jaci.2023.08.036

Kathleen Baysac, PhD ^a, Guangping Sun, PhD ^b, Hiroto Nakano, MD, PhD ^a, Elizabeth G. Schmitz, BS ^a, Anthony C. Cruz, BS ^a, Charles Fisher, BA, MAT ^a, Alexis C. Bailey, MD ^a,
PLCG2-Immune Dysregulation Working Group^{^∗}
A listing of the working group membership is provided in the Acknowledgments section.
Jordan K. Abbott, MD, MA, Juan Carlos Aldave Becerra, MD, Eric J. Allenspach, MD PhD, Kristian Assing, MD, PhD, T. Prescott Atkinson, MD, PhD, Umair A. Bargir, MD, Sarah K. Baxter, MD, PhD, Jenna R.E. Bergerson, MD, Ranjan Bista, MD, Stephane Blanche, MD, Lenore M. Buckley, MD, Manish Butte, MD, PhD, Benjamin Carcamo, MD, Shanmukhaiah Chandrakala, MD, Karin Chen, MD, Sheva Chervinskiy, DO, Ivan K. Chinn, MD, Hey J. Chong, MD, PhD, Kara E. Coffey, MD, Andrew P. Copland, Edward W. Cowen, MD, MHSc, Guilhem Cros, MD, Jean Jacques De Bruycker, MD, FRCPC, Maria Teresa de la Morena, MD, Mohammed Ehlayel, MBBS, Lisa R. Forbes Satter, MD, Erwin W. Gelfand, MD, Olivier Gilliaux, MD, Sara C. Glover, DO, Mark Gorman, MD, Thomas A. Griffin, MD, PhD, Bodo Grimbacher, MD, PhD, Alejandro A. Gru, MD, Elie Haddad, MD, PhD, Jerome Hadjadj, MD, PhD, Joud Hajjar, MD, PhD, Fabian Hauck, MD, PhD, Timo Hautala, MD, PhD, Steven M. Holland, MD, Elena W.Y. Hsieh, MD, Florence Ida Hsu, MD, Emmanuel Jacquemin, MD, PhD, Ankur Kumar Jindal, MD, Stacy A. Kahn, MD, Michael D. Keller, MD, Roger H. Kobayashi, MD, Christa Krupski, DO, MPH, Allyson Larkin, MD, Monica G. Lawrence, MD, Manisha Madkaikar, MD, Marion Malphettes, MD, Timi Martelius, MD, PhD, Mehek Mehta, MD, Dean D. Metcalfe, MD, Isabelle Meyts, MD, PhD, Naveen Nannapaneni, MD, J. Gonzalo Ocejo Vinyals, MD, PhD, Kenneth Olivier, MD, Amanda K. Ombrello, MD, Jordan S. Orange, MD, PhD, Nathan Rabinovitch, MD, MPH, Christine K. Rauscher, MD, Ann Redfern, PNP, Paul R. Reynolds, PhD, Frederic Rieux-Laucat, MD, PhD, Elizabeth Secord, MD, Filiz O. Seeborg, MD MPH, Mikko R.J. Seppänen, MD, PhD, Irini Sereti, MD, PhD, Daniel S. Shin, MD, Junghee J. Shin, MD, PhD, Scott B. Snapper, MD, PhD, Deepti Suri, MD, DNB, Sirikarn Tangcheewinsirikul, MD, Akaluck Thatayatikom, MD, Troy Torgerson, MD, PhD, Fabien Touzot, MD, Gulbu Uzel, MD, Markku Varjosalo, PhD, Dewton F.P. Vasconcelos, MD, PhD, Horst von Bernuth, MD, PhD, Thomas Walsh, PhD, Jolan E. Walter, MD, PhD, Brant R. Ward, MD, PhD, Helmut Wittkowski, MD, Christian A. Wysocki, MD, PhD

Emily Mace, PhD ^c, Joshua D. Milner, MD ^c,^{^{‡
Co-senior authors.}}, Michael J. Ombrello, MD ^a,^⁎,^{^{‡
Co-senior authors.}}
^a Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md
^b Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^c Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY

^∗Corresponding author: Michael J. Ombrello, MD, Translational Genetics and Genomics Section, Intramural Research Program, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Dr, 13C103A, Bethesda, MD 20892.Translational Genetics and Genomics SectionIntramural Research ProgramNational Institutes of Arthritis and Musculoskeletal and Skin DiseasesNational Institutes of Health10 Center Dr13C103ABethesdaMD20892

Graphical abstract

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Abstract

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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Key words : Phospholipase C gamma 2, immune dysregulation, primary immune deficiency, variants of uncertain significance, autoinflammation, antibody deficiency

Abbreviations used : APLAID, BCR, CADD, CMV, ERK, G-CSF, gnomAD, GOF, IBD, ID, ILD, LOF, NK, pERK, PLAID, PLCG2, SiPhy, VUS, WT

Plan

Methods

Study subjects and PLCG2 variants

In silico assessment of PLCG2 variants

Construction of plasmids

Cell culture and transfection

Calcium flux analysis

Intracellular ERK phosphorylation analysis

Western blot analysis

Quantitative RT-PCR

NK-cell cytotoxicity assay

Statistical analysis

Results

Novel and ultrarare PLCG2 variants identified in people with ID

In silico examination of PLCG2 variants

Most observed PLCG2 variants alter B-cell activation

Phenotypes of PLCG2 variants associated with reduced B-cell activation

Autosomal-dominant transmission of haploinsufficiency of PLCG2 featuring autoinflammation, bacterial and viral infection, and NK-cell dysfunction

Novel GOF and constitutive activation variants in PLCG2

Discussion

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Vol 153 - N° 1

P. 230-242 - janvier 2024 Retour au numéro

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Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency
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PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants - 04/01/24

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Abstract

Background

Objective

Methods

Results

Conclusions

Plan

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