SOCS1 Haploinsufficiency in a Patient with Granulomatous Interstitial Lung Disease and Inflammatory Bowel Disease-like Disease

Introduction SOCS1 haploinsufficiency is an inborn error of immunity with dysregulated JAK–STAT signaling and heterogeneous autoimmune, infectious, and inflammatory phenotypes; its spectrum and management remain unclear. Methods We report a 29-year-old woman with a novel heterozygous SOCS1 variant (c.494C>T; p.Pro165Arg) identified by whole-exome sequencing. Variant impact was assessed in silico (CADD, conservation mapping, AlphaFold3, PremPS) and functionally by measuring total and phosphorylated STAT1 expression in patient vs control cells at baseline and after IFN-γ stimulation. We also reviewed data from 20 previously reported SOCS1-deficient patients. Results The patient had granulomatous lymphocytic interstitial lung disease (GLILD), rheumatoid arthritis, IBD-like enteropathy, and hypogammaglobulinemia, initially diagnosed with CVID. GLILD responded to rituximab; sirolimus was ineffective for enteropathy. Segregation revealed an asymptomatic father carrying the same variant. The patient was found to have an additional heterozygous TACI gene variant. Post-stimulation flow cytometry showed higher STAT1 (24.7 vs 5.8 MFI) and p-STAT1 (43.4 vs 2.4 MFI) levels; however, these differences were not statistically significant (p>0.05). Structural modeling predicted SH2-domain destabilization (ΔΔG +1.16 kcal/mol). Literature synthesis for SOCS1 deficiency patients (n=21) showed median symptom onset of 8 years (range 5 months–44 years), autoimmune diseases (immune thrombocytopenia, psoriasis, etc.), and frequent immunophenotypic abnormalities: lymphopenia 4/8 (50%); high IgE 5/7 (71.4%); low CD3+ 11/17 (64.7%); CD4+ 6/19 (31.5%); CD8+ 5/17 (29.4%); B cells 5/17 (29.4%); and NK cells 4/19 (21%). Conclusion SOCS1 haploinsufficiency presents heterogeneous phenotypes with variable penetrance. Early genetic testing and targeted interventions, such as JAK inhibitors or cytokine-blocking biologics, may improve outcomes.