Background: Suppressor of cytokine signaling 1 (SOCS1) insufficiency is a recently discovered inborn error of immunity affecting negative regulation of cytokine signaling. Initial reports described variable clinical phenotypes of immune dysregulation, but also asymptomatic carriers.Methods: We combined a patient registry with a population-based analysis to describe manifestations, individual disease trajectories including treatment responses and disease penetrance in SOCS1 insufficiency.Findings: The registry captured 62 symptomatic and 5 asymptomatic individuals from 12 countries. 27 mono-allelic variants were identified, 20 functionally validated. In the UK biobank, we identified 52 additional individuals carrying 8 variants documented in the registry or 4 other high-impact mutations and analyzed their ICD10 diagnoses. Among a wide spectrum of phenotypes presenting across all ages, atopic disorders were most frequent (50%) followed by inflammatory gastrointestinal (45%) and skin manifestations (39%), autoimmune cytopenia (37%) and lymphoproliferation (34%). Rheumatological manifestations (33%) included systemic lupus erythematosus, arthritis, vasculitis, Sjögren syndrome and spondyloarthritis, with autoantibodies in most affected patients. Inflammatory lung, liver, kidney or brain disease were less frequent. One-third of patients had at least 3 different manifestations. Most patients had several immunosuppressive treatments, 14 received a JAK inhibitor with at least partial remission in 12. Among 52 UK biobank individuals, only 30 showed potentially SOCS1-related manifestations. Female predominance was observed among symptomatic (58 female/34 male), but not among asymptomatic (10 female/17 male) variant carriers.Interpretation: Frequent atopic and rheumatologic manifestations separate SOCS1 insufficiency from other autoimmune-lymphoproliferative disorders. Penetrance is incomplete and higher in females. JAK inhibition emerges as promising targeted therapy.

Keywords: SOCS1 insufficiency, registry, UK biobank, inborn error of immunity, autoimmunity, allergy