Submission Details

STAT3 was first reported in relation to early-onset multisystem autoimmune disease in 2014 (PMID: 25038750). STAT3 gain-of-function (GOF) variants are associated with lymphoproliferation, autoimmunity and hypogammaglobulinemia. There is a wide array of clinical symptoms observed and is hypothesized to be due to differences in the variant’s location in functional domains of STAT3 (PMID: 31770611). Some STAT3 GOF mutations exhibit incomplete penetrance in the population, suggesting that STAT3 GOF mutations alone are not enough to cause disease in some cases. Over 49 variants have been reported in the literature (PMID: 34366294). For this curation, 10 variants in 10 probands in 3 publications (PMIDs: 25359994, 25349174, 25038750) are included. The maximum score for genetic evidence (12 pts.) was reached in this curation and no further variants are included.

This gene-disease association is also supported by expression studies, functional assays, and animal models. STAT3 is important in cytokine and growth factor signaling. STAT3 is phosphorylated by receptor associated Janus kinases (JAK), causing formation of STAT homo- or heterodimers, followed by translocation into the nucleus to act as a transcription factor. STAT3 is widely expressed and is important for many processes in immunity, cell growth and apoptosis. The exact mechanism leading to STAT3 GOF disease is unknown due to the wide array of functions STAT3 can perform. However, there is evidence STAT3 GOF variants impact immune cell function, leading to autoimmunity. STAT3 GOF variants lead to higher levels of functional STAT3 in patient cells (PMID: 25359994), and lead to increases in negative regulators of cytokine signaling, suggesting over-activity of immune cells (PMID: 25359994). Supporting this finding, groups have shown increased differentiation of T helper 17 cells (TH17) in STAT3 GOF patients (PMID: 26343524), a cell type that is implicated in mediating many autoimmune diseases. Lastly, the generation of a mouse model substituting a STAT3 patient variant led to increased incidence of diabetes mediated by CD8 T cells (PMID: 34115115), as identified in a subset of STAT3 GOF patients. Altogether, published evidence suggests the STAT3 GOF variants are leading to immune cells with increased reactivity and likelihood to cause autoimmunity. However, more mechanistic studies are needed to fully understand the range of clinical symptoms seen in patients.

Of note, somatic STAT3 GOF mutations have been identified in cases of large granulocytic leukemia (LGL) (PMIDs: 23207521, 22591296) and likely represent a pathogenic driver of this process. There have been reports of individuals with germline STAT3 GOF developing LGL, though the prevalence of LGL cases caused by germline STAT3 GOF variants is unknown. Future review of this curation will need to assess the relationship between LGL and germline STAT3 GOF variants as more research is performed.

In summary, STAT3 is definitively associated with early-onset multisystem autoimmune disease and immune deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on January 20, 2022 (SOP Version 8).