Submission Details

PIK3CG was first reported in relation to immunodeficiency 97 with autoinflammation in 2019 (Takeda AJ, et al., 2019, PMID: 31554793) and a second patient reported in 2020 (Thian M, et al., 2020, PMID: 33054089). Each patient is compound heterozygous for partial to full loss of function variants, for a total of four variants (3 missense and one frameshift). PIK3CG encodes the p110γ catalytic subunit of PI3Kγ, which phosphorylates PtdIns(4,5)P2 to produce PtdIns(3,4,5)P3, a versatile second messenger that potently activates diverse signaling cascades to coordinate the cellular response to growth factors, cytokines, chemokines, and antigen receptor stimulation, among other inputs. Data are consistent with a mechanistic model in which deficiency in PI3Kγ results in GSK3-dependent overproduction of IL-12 and IL-23 by myeloid cells, leading to increased T cell accumulation in tissues that, together with defective immunoglobulin production and reduced regulatory T cells, underlies disease pathophysiology. Experimentally, this gene-disease relationship is supported by its increased expression in tissues involved in immune responses (PMID: 24014027) and function as a phosphatidylinositol 3-kinase (PMID: 24014027) which participates in T cell receptor–induced T cell activation (PMID: 17998387) which was observed in both patient and knock out cells (PMID: 33054089). Additionally, the defects in patient T cells are rescued with wild type protein (PMID: 33054089). Finally, multiple mouse models have been reported (PMID: 10669416, PMID: 31554793) that recapitulate the disease. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.