Lower Disease Severity in STAT3 GOF Patients with Mild Potency Variants

Germline gain-of-function (GOF) variants in the transcription factor STAT3 are associated with early-onset, multisystem autoimmunity, lymphoproliferation, and immune dysregulation. Although STAT3 hyperactivation is a defining feature of this disorder, any relationship between the potency of STAT3 GOF variants and clinical presentations remains undefined. We hypothesized that variants with higher potency would result in more severe disease. Patients with STAT3 GOF were grouped into “mild” or “moderate to extreme” potency. Potency was determined by the fold increase in STAT3 transcriptional capacity of a variant relative to wild-type STAT3, determined using a standard luciferase. In a subset of patients for whom primary biosamples were available, lymphoblastoid cell lines (LCLs) were generated. LCLs were stimulated with IL-21 to assess STAT3 activation (phospho-Y705) using flow cytometry.Transcription of the STAT3-driven gene SOCS3 following IL-21, in the absence or presence of JAK inhibitors, was also determined using real-time PCR. Clinical, immunophenotype, and treatment data for 191 previously reported patients with STAT3 GOF (1), representing 72 unique variants, were evaluated. STAT3 GOF variants ranged greatly in potency (median 16.6, interquartile range [IQR] 4.2, 46.5).There were no high to extreme potency variants in the N-terminal or transactivation domains. In LCLs from 7 patients, activated STAT3 (MFI of phospho-STAT3) correlated with potency (r2 = 0.78, p < 0.0001). Patients carrying low potency variants (<5x wild-type, 72/191 patients [38%]) were older at symptom onset (8 vs. 4 years, p = 0.001), had less total organ systems involved (4 vs. 4.8, p = 0.003), were given less cumulative medications (1.8 vs. 2.4, p = 0.022), and were less likely to be deceased (5.6% vs. 16%, p = 0.039). Patients with low potency variants in this historical cohort were also less likely to have been prescribed tocilizumab (13% vs. 36%, p < 0.001) or a JAK inhibitor (14% vs. 33%, p = 0.004).Transcription of SOCS3 in 10 LCLs was terminated by the addition of a JAK inhibitor (p < 0.01 for most variants). In summary, STAT3 GOF variant potency varies widely compared to wild-type STAT3. Overall, patients carrying mild potency variants appeared to have less severe disease. Quantitative functional assessment of STAT3 variants may assist with the prognosis and management of STAT3 GOF syndrome.