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This study investigates the pathogenic mechanism of a novel variant of <jats:italic>PLCG2<\/jats:italic> in a patient with APLAID syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing and Sanger sequencing were used to identify the pathogenic variant in the patient. Single\u2010cell RNA sequencing, immunoblotting, luciferase assay, inositol monophosphate enzyme\u2010linked immunosorbent assay, calcium flux assay, quantitative PCR, and immunoprecipitation were used to define inflammatory signatures and evaluate the effects of the <jats:italic>PLCG2<\/jats:italic> variant on protein functionality and immune signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a novel de novo variant, <jats:italic>PLCG2<\/jats:italic> p.D993Y, in a patient with colitis, pansinusitis, skin rash, edema, recurrent respiratory infections, B\u2010cell deficiencies, and hypogammaglobulinemia. The single\u2010cell transcriptome revealed exacerbated inflammatory responses in the patient's peripheral blood mononuclear cells. Expression of the D993Y variant in HEK293T, COS\u20107, and <jats:italic>PLCG2<\/jats:italic> knock\u2010out THP\u20101 cell lines showed heightened PLC\u03b32 phosphorylation; elevated inositol\u20101,4,5\u2010trisphosphate production and intracellular Ca<jats:sup>2+<\/jats:sup> release; and activation of the MAPK, NF\u2010\u03baB, and NFAT signaling pathways compared with control\u2010transfected cells. In vitro experiments indicated that the D993Y variant altered amino acid properties, disrupting the interaction between the catalytic and autoinhibitory domains of PLC\u03b32, resulting in PLC\u03b32 autoactivation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings demonstrated that the <jats:italic>PLCG2<\/jats:italic> D993Y variant is a gain\u2010of\u2010function mutation via impairing its autoinhibition, activating multiple inflammatory signaling pathways, thus leading to APLAID syndrome. This study further broadens the molecular underpinnings and phenotypic spectrum of PLC\u03b32\u2010related disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42948","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T00:39:10Z","timestamp":1720139950000},"page":"1670-1678","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Characterization of a Novel Pathogenic <scp><i>PLCG2<\/i><\/scp> Variant Leading to APLAID\u00a0Syndrome Responsive to a TNF Inhibitor"],"prefix":"10.1002","volume":"76","author":[{"given":"Zhaohui","family":"Yang","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu Laboratory Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panfeng","family":"Tao","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital, Zhejiang 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