PLCG1

Inheritance Pattern: AD

Disease ID:MONDO:0957790

Submitter: ClinGen

A monogenic association between PLCG1 and human disease was first reported in 2023 in an individual with an autosomal dominant syndrome featuring autoimmune anemia and thrombocytopenia, bleeding diathesis, and lymphadenopathy (PMID: 37422272). The condition was later termed “Immune Dysregulation, Autoimmunity, Autoinflammation” (OMIM: 620514; MONDO: 0957790). This individual also had multiple autoantibodies (direct antiglobulin, anti-platelet, ANA 1:1000, anti-SSA, anti-nucleosome), decreased NK cells, low C3/C4, and elevated ESR. To date, eight individuals with heterozygous PLCG1 variants have been reported, six with immune phenotypes. All additional cases were described in a case series reporting variable immune, vision, hearing, and cardiac features in autosomal dominant PLCG1 disease (PMID: 40862571). Reported immune manifestations include recurrent respiratory infections, pneumococcal sepsis, severe EBV infection, recurrent immune thrombocytopenia, lymphadenopathy, arthritis/synovitis, recurrent encephalopathy, impaired polysaccharide vaccine responses, and decreased IgA and IgG2. Non-immune features include blindness, sensorineural hearing loss, septal defects, and motor and speech delays. Phenotypic variability is high, including among four related individuals with the same variant, indicating variable expressivity. The mechanism of pathogenicity is gain of function. Multiple patient variants show increased PLCG1 enzymatic activity, elevated inositol phosphate production, hyperactivation of NFAT, NF-κB, and AP-1 pathways, and increased inflammatory cytokines (PMIDs: 37422272, 40862571, 27369867). A PLCG inhibitor rescues these abnormalities, including excess MAPK phosphorylation and cytokine expression (PMID: 37422272). Additional supporting evidence includes PLCG1 expression in many immune cell types (PMIDs: 22837484, 15372077, 1281218) and impaired inositol phosphate production, proliferation, and cytokine responses in PLCG1-deficient T cells (PMID: 20123962). Unscored but relevant evidence comes from a mouse model of constitutive PLCG2 activation (PMID: 15845450). PLCG2 is highly homologous to PLCG1, functions in analogous signaling pathways, and is itself associated with GOF autoinflammatory disease (PLAID and APLAID). PLCG2-GOF mice develop arthritis, uveitis, and glomerulonephritis, and show increased B-cell Ca²⁺ flux and anti-DNA antibodies. In summary, there is moderate evidence linking PLCG1 to an autosomal dominant, gain-of-function disorder with variable expressivity of immune dysregulation, as well as hearing, vision, and cardiac features. Given that “immune dysregulation” encompasses “autoimmunity” and “autoinflammation”, we propose the simplified disease name “PLCG1 Immune Dysregulation.” However, given phenotypic variability and sparsity of published cases, the core immune features of this condition remain incompletely defined, and additional case descriptions with detailed immune phenotyping are needed.

Inheritance Pattern: AD

Disease ID:MONDO:0957790

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0957790

Submitter: PanelApp Australia