PLCG2 associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants.

Background: Pathogenic variants of PLCG2 cause 2 related forms of autosomal dominant immune dysregulation, PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID). Since describing these conditions, many PLCG2 variants of uncertain significance (VUS) have been identified by clinical sequencing of patients with diverse features of immune dysregulation.
Objective: 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 eGFP-PLCG2 plasmid, which was overexpressed in Plcg2-deficient DT-40 B-cells. BCR-induced calcium flux and ERK 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). Susceptibilty to infection and autoinflammation were common with both GOF and LOF variants, while a new phenotypic cluster consisting of humoral immune deficiency, autoinflammation, susceptibility to herpesviral infection and natural killer (NK) cell dysfunction were observed in association with multiple heterozygous LOF variants detected in both familial and sporadic cases. In some cases, PLCG2 variants produced greater effects in NK cells than B-cells.
Conclusion: This work expands the genotypic and phenotypic associations with functional variation in PLCG2, including a novel form of immune dysregulation 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.
(Copyright © 2023. Published by Elsevier Inc.)