Submission Details

STAT6 was first reported in relation to autosomal dominant hyper-IgE syndrome 6 in 2023 (Suratannon N, et al., 2023, PMID: 36216080). This is an immunologic disorder characterized by early-childhood onset of severe refractory atopic dermatitis, IgE-mediated food and drug allergies, asthma, and eosinophilic esophagitis. Laboratory studies show increased serum IgE levels and eosinophilia. Additional features may include allergic rhinitis, recurrent secondary infections (bacterial, viral, fungal), and short stature. It is caused by caused by heterozygous gain of function mutations; 11 missense variants reported in 12 probands in 3 publications (PMIDs: 36216080, 36884218, 36758835). This gene-disease relationship is further supported by experimental evidence including its biochemical function in mediating the effects of IL4 (PMID: 8085155), a key cytokine necessary for type 2 differentiation of CD4+ T cells (TH2) and B cells, cell proliferation, and class switching to IgE. Functional alteration in patient cells confirmed a significant increase of TH2 lymphocytes and increased IL-4 production, while transcriptomic changes were found in D419G-transducted cells (PMID: 36884218). A protein interaction with STAT3 (definitively related to hyper-IgE syndrome 1) has been reported (PMID: 20211142). In addition, a gain of function mouse model shares a number of key features of the allergic diathesis, including elevated serum IgE and chronic atopic dermatitis (PMID: 12646608). In summary, there is strong evidence to support the relationship between STAT6 and autosomal dominant hyper-IgE syndrome 6. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted.