Genotype-Phenotype Correlation in PLCG2 Mutation-Positive Autoinflammatory Disease

Project no. 32697 · Status: Kapanmış (Yayın bekleniyor) · 2025

Summary

Introduction – Aim: Autoinflammatory diseases (AID) are a group of disorderscharacterized by recurrent systemic inflammation attacks in the absence of evidence forinfection or autoimmunity. These conditions are driven by genetic mutations that disrupt keyimmune signaling pathways. While mutations in the MEFV and NLRP3 genes are commonlyassociated with AID, recent studies suggest that mutations in the PLCG2 gene, whichencodes phospholipase C gamma 2, may also contribute to disease pathogenesis. PLCG2plays a crucial role in intracellular calcium signaling and the production of secondmessengers that regulate immune responses, mediating activation of B cells, natural killer(NK) cells, and myeloid cells.In this study, we prospectively evaluated pediatric patients (ages 0–18) presenting toour clinic with suspected autoinflammatory disease symptoms (recurrent fever, abdominalpain, myalgia, and arthralgia). Using next-generation sequencing (NGS), we investigatedmutations associated with autoinflammatory diseases, including MEFV, NLRP3, PLCG2,NLRC4, IL1RN, PSMB8, TNFRSF1A, MVK, PSTPIP1, NOD2, NLRP1, CARD8, NLRP12,CARD14, CECR1, LPIN2, TNFRSF11A, TMEM173, TNFAIP3, OTULIN, IL23R, TREX1,IL12RB, ELANE, NALP12, and ILIORA. Among these, only patients found to have apositive mutation in PLCG2 were further evaluated for genotype-phenotype correlation basedon clinical presentation and physical examination findings at initial admission. Clinicalfeatures and disease severity were analyzed and compared with known phenotypes associatedwith PLCG2 mutations, such as PLAID (PLCG2-associated antibody deficiency and immunedysregulation), APLAID, and FCAS 3 (Familial Cold Autoinflammatory Syndrome 3).Materials and Methods: A total of 40 cases were included in the study. Informedinterviews were conducted with patients and their parents, and a case report form wascompleted, documenting details such as age at onset of attacks, associated symptoms, andtheir frequency. Two milliliters of blood were collected in EDTA tubes from each patient forgenetic analysis. NGS (Next Generation Sequencing) was performed at the MolecularMedicine and Genetics Laboratory of Ege University. Results were analyzed using SPSSsoftware.The primary aim was to assess the genotype-phenotype relationship in patients with apositive PLCG2 mutation and negative results for MEFV and NLRP3 mutations.VIIIResults: In total, 40 patients with suspected autoinflammatory disease wereevaluated. Mutations associated with autoinflammatory diseases were screened, and 24patients were identified with positive PLCG2 mutations while other tested genes werenegative. These 24 patients were included in the final analysis. Among them, 18 differentmutations in the PLCG2 gene were detected.Conclusion: PLCG2 encodes a phospholipase enzyme that plays a critical role in B-cell signaling. While germline mutations in PLCG2 have been associated in the literaturewith immunodeficiency and neurodegenerative disorders, somatic mutations have beenimplicated in lymphoproliferative disorders and resistance to BTK inhibitors. In our study,the finding of PLCG2 mutations as the only positive result in patients presenting withautoinflammatory disease symptoms highlights the potential role of PLCG2 not only in theadaptive immune system but also in the innate immune response. Moreover, the presence ofclinically significant manifestations in our cohort associated with PLCG2 variants previouslyreported as benign or variants of uncertain significance (VUS) suggests a possible pathogenicrole. Additionally, previously unreported PLCG2 mutations were identified, and theirassociated clinical phenotypes were described.

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