For instance, despite the fact that most STAT3 GOF variants have much greater than wild-type transcriptional capacity in a luciferase assay system at baseline, STAT3 GOF variants do not appear to lead to constitutive activation (i.e., phosphorylation) of STAT3 in peripheral blood mononuclear cells (PBMCs) of patients with STAT3 GOF syndrome, e.g., in cells that are not transfected or transformed (5, 7–11). The gene discussed is STAT3; the disease is Down syndrome.