PLCG2 variants are frequently detected in people with immune dysregulation, but whether individual variants cause or contribute to immune abnormalities is unknown. Dominant variants of PLCG2 in humans lead to aberrant leukocyte signaling with variably expressed symptoms that include low serum immunoglobulin levels, recurrent sinopulmonary infections, autoimmunity-related cold rash, and sterile inflammation. In this study, the researchers used an in vitro approach to characterize the effects of 60 PLCG2 variants of uncertain significance identified in a group of 76 people with immune dysregulation. Over 70% of the variants result in PLCG2-dependent altered function, and most of the variants led to reduced PLCG2 activity, which suggests a new class of PLCG2 mutation and a novel form of PLCG2-associated immune dysregulation.

What is exciting about this article?

This study of people with immune dysregulation and PLCG2 variants suggests for the first time that genetic variants of PLCG2 that reduce its functional capacity can cause an autosomal dominant form of immune dysregulation. This finding expands our understanding of genotypic and phenotypic PLCG2-associated immune dysregulation. It also highlights the need for more diverse assays to accurately assess cell-type specific effects of PLCG2 variants on human disease.

Grant Support


Research Areas:

Autoimmunity Genetics and Genomics


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

Baysac K, Sun G, Nakano H, Schmitz EG, Cruz AC, Fisher C, Bailey AC, PLCG2-Immune Dysregulation Working Group, Mace E, Milner JD, Ombrello MJ
J Allergy Clin Immunol.
2024 Jan;
doi: 10.1016/j.jaci.2023.08.036
PMID: 37769878

Research reported in this publication was supported by the Intramural Research Program of the NIHʼs National Institute of Arthritis and Musculoskeletal and Skin Diseases.