D2.351 - Germline Variant in the GNAI2 Gene Associated with Severe Immune Dysregulation and Autoimmune Hemolytic Anemia in a Pediatric Patient

Background. Inborn Errors of Immunity (IEIs) represent a highly heterogeneous group of disorders, with the number of associated genes expanding by approximately 30 genes every two years. According to the most recent classification, over 500 genes have now been linked to IEIs, conferring susceptibility to recurrent infections, immune dysregulation, bone marrow failure, and malignancies [1]. Germline variants in the GNAI2 gene are not yet included in the IEI classification; however, a 2024 study reported 20 patients from 18 unrelated families worldwide carrying rare heterozygous variants in the GNAI2 gene, with clinical features indicating immune system involvement in approximately 90% of cases, characterized by recurrent, unusual, and/or severe infections [2].

Methods. We report a clinical case of a two-year-old non-Finnish European girl diagnosed with Coombs-positive autoimmune hemolytic anemia who was admitted to Belarusian Research Center for Pediatric Oncology, Hematology and Immunology for treatment and genetic testing. Whole-exome sequencing was performed on the DNBSEQ-G50 platform (MGI, China) using KAPA HyperCap Target Enrichment Probes (Roche, USA). Written informed consent was obtained from the patient’s parents.

Results. The patient’s medical history included recurrent respiratory infections, otitis media, rotavirus infection, and pneumonia. Immunological evaluation revealed neutrophilia during infection, markedly increased B-cell counts (60.8%; absolute count 3,356 × 10⁹/L), reduced thymic emigrants (29%), and age-appropriate immunoglobulin levels. Following the first course of rituximab therapy, a partial hematological response was achieved; however, disease progression occurred two months later, with worsening cytopenias, hepatosplenomegaly, hemophagocytic lymphohistiocytosis, coagulopathy, severe infectious complications, enteropathy, and respiratory failure requiring intensive care. Genetic testing identified a heterozygous variant in the GNAI2 gene: (NM_002070.4) c.545C>T, p.Thr182Ile, classified as likely pathogenic (VarSome) and pathogenic (ClinVar: October 12, 2025). Variants affecting amino acid Thr182 in the GNAI2 gene have been reported to be associated with more extensive immune system involvement due to additional inflammatory and autoimmune manifestations [2].

Conclusion. This case supports the role of GNAI2 variants in severe immune dysregulation with autoimmune and hyperinflammatory features. Given the pronounced inflammatory response and severe infections, IL-1β inhibitor therapy was initiated with ongoing assessment of clinical response. The patient remains in critical condition in the intensive care unit.

References

1. Poli M. et al. Human inborn errors of immunity: 2024 update on the classification. J Hum Immun. 2025;1(1):e20250003. DOI: 10.70962/jhi.20250003.
2. Ham H. et al. Germline mutations in a G protein identify signaling cross-talk in T cells. Science. 2024;385(6715):eadd8947. DOI: 10.1126/science.add8947.