Submission Details

STAT3 was first reported in relation to autosomal dominant hyper IgE syndrome (HIES) in 2007 (PMID: 17881745). STAT3 loss-of-function (LOF) variants are associated with elevated serum IgE, eczema, and recurrent skin and respiratory tract infections. Patients also have other clinical manifestations that display variable expressivity, including eosinophilia, chronic mucocutaneous candidiasis, systemic allergic manifestations, and extra-hematopoietic features. Over 143 heterozygous variants of STAT3 had been reported in patients with HIES (PMID: 34137790). These 143 variants include 114 missense mutations, 21 in-frame indels, and 8 nonsense or frameshift indels. Deep intronic variants have also been identified in STAT3 and have been shown to result in dominant negative (DN) effect on STAT3 function (PMID: 31346092). Most of the mutations cluster to the DNA binding domain and SH2 domain. For this curation, 14 variants in 14 probands in 4 publications are included (PMID: 17676033, 18602572, 22751495, 31346092). 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 functional assays, animal models and rescue experiments. After receptor-ligand binding, 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. Mechanistically, STAT3 mutated HIES is driven by dominant negative (DN) variants resulting in reduced STAT3 functionality in cells involved with immunity, osteogenesis, and other biological processes. Using a luciferase based STAT3 transcriptional activity assay, transfection of STAT3 LOF variants into STAT3 sufficient cells demonstrated almost all variants cause a dominant negative (DN) reduction in STAT3 activity (PMID: 34137790). No cases of STAT3 LOF variants leading to haploinsufficiency were identified using this experimental approach. HIES patients with STAT3 LOF variants demonstrate variable levels of pSTAT3 compared to WT, but reproducibly show B cell dysfunction, decreased T helper 17 (Th17) CD4 T cell differentiation and elevated frequencies of IgE+ B cells (PMID: 33045280, 18602572). Two distinct mouse models were curated to supported STAT3 LOF variants as a mechanism of HIES. These two models demonstrated increased IgE production, increased susceptibility to infection, and decreased TH17 CD4 T cell responses, replicating patient phenotypes (PMID: 31026806, 24632714). Rescue experiments using CRISPR base editing demonstrated increased pSTAT3 levels, STAT3 activity and increased STAT3-dependent cytokine signaling following reversion (PMID: 33876960). In a patient with HIES, HSCT resulted in normalization of TH17 CD4 T cell number, serum IgE levels, STAT3-dependent cytokine signaling and improvement in other HIES associated clinical features (PMID:25962528).

In summary, STAT3 is definitively associated with hyper-IgE syndrome. 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 the meeting date, December 16, 2021 (SOP Version 8).

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 pSTAT3 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, STAT3 GOF mutations have been identified in cases of large granulocytic leukemia (LGL) (PMID: 23207521, 22591296), and likely represent a pathogenic driver of this somatic 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. 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 December 16, 2021 (SOP Version 8).