Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond

Signal transducer and activator of transcription (STAT)-6 is a transcription factor central to pro -allergic immune responses, although the function of human STAT6 at the whole -organism level has long remained unknown. Germline heterozygous gain -of -function (GOF) rare variants in STAT6 have been recently recognized to cause a broad and severe clinical phenotype of early -onset, multi -system allergic disease. Here, we provide an overview of the clinical presentation of STAT6-GOF disease, discussing how dysregulation of the STAT6 pathway causes severe allergic disease, and identifying possible targeted treatment approaches. Finally, we explore the mechanistic overlap between STAT6-GOF disease and other monogenic atopic disorders, and how this group of inborn errors of immunity (IEIs) powerfully inform our fundamental understanding of common human allergic disease.