The following is a summary of “PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants,” published in the January 2024 issue of Allergy & Immunology by Baysac, et al.

Phospholipase C gamma 2 (PLCG2) variants are known to cause autosomal-dominant immune dysregulation (ID), including PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID). Despite identifying these conditions, many PLCG2 variants of uncertain significance have been discovered through clinical sequencing of patients with various ID features. For a study, researchers sought to functionally classify PLCG2 variants and investigate genotype-function-phenotype relationships, utilizing clinical data from patients with PLCG2 variants obtained through a standardized questionnaire.

PLCG2 variants were generated by mutagenesis of enhanced green fluorescent protein (EGFP)-PLCG2 plasmid, which was then overexpressed in Plcg2-deficient DT-40 B cells. B-cell receptor-induced calcium flux and extracellular signal-regulated kinase phosphorylation were assessed by flow cytometry. Additionally, stimulation-induced calcium flux was sometimes measured in primary patient cells.

Three-fourths of PLCG2 variants exhibited functional alterations in B-cell activation in vitro. Thirteen variants led to a gain of function (GOF), while most functional variants were characterized as monoallelic loss of function (LOF). Both GOF and LOF variants were associated with susceptibility to infection and autoinflammation. Furthermore, carriers of multiple heterozygous LOF variants displayed a new phenotypic cluster featuring humoral immune deficiency, autoinflammation, susceptibility to herpesvirus infection, and natural killer cell dysfunction. In certain cases, PLCG2 variants exerted greater effects in natural killer cells than B cells.

The study broadened the understanding of the genotypic and phenotypic associations with functional variation in PLCG2. It identified a novel form of ID associated with carriers of heterozygous loss of PLCG2 function and underscored the necessity for diverse assays to assess the impact of PLCG2 variants on human disease.

Reference: jacionline.org/article/S0091-6749(23)01200-9/abstract