Submission Details

SOCS1 was first reported in relation to autosomal dominant autoinflammatory syndrome with immunodeficiency in 2020 (Thaventhiran et al., PMID: 32499645; Lee et al, PMID: 32853638; Hadjadj et al, PMID 33087723). An autosomal dominant, immune dysregulation disorder with incomplete penetrance characterized by autoimmmunity (autoimmune cytopenia, hemolytic anemia, thrombocytopenia) and lymphoproliferation. Additional variable features may include autoimmune thyroiditis, psoriasis or eczema, nephritis, hepatitis, and symptoms of systemic lupus erythematosus. Immunodeficiency is present in some patients. Disease onset is usually in the first decades of life, although later onset has been reported.

Twelve variants (missense, nonsense) that have been reported in probands in five publications (PMIDs: 39840313, 39005503, 33087723, 32853638, 32499645) are included in this curation. SOCS1 has only one coding exon therefore non-mediated decay is not predicted for any variant. Several probands present with thrombocytopenia, hepatitis, recurrent infections, neutropenia, while others have been diagnosed with common variable immunodeficiency. Because SOCS1 haploinsufficiency has incomplete penetrance, the phenotypic features of probands, even within the same families, exist on a wide spectrum of severity.

This gene-disease relationship is also supported by animal models, functional assays, and protein interactions. Model systems in mice (PMIDs: 10490099, 11371356) SOCS1 knockout mice exhibit severe inflammation in the neonatal period which includes immune-mediated hepatitis, and thrombocytopenia, features shared by haploinsufficient humans. Injury to the liver is shown in complete SOCS1 knockout in mice predicts that without cross-talk inhibition via SOCS-1, IL-4 and IFN-γ signaling there is damage to various organs, localized by other factors such as susceptibility to infection. SOCS1 plays a role in downregulating cytokine signaling by inhibiting the activity of Janus kinases (JAKs), key components of the JAK/STAT signaling pathway. Functional alteration studies (PMID: 34421895) show that when SOCS1 had reduced protein expression, organ damage through chronic infections and/or autoimmunity is predictive. Meanwhile, increased activity in the FAK – AKT – RS6K pathway may explain the accumulation of autoimmunity. Biochemical function (PMID: 9341160) and protein interactions (PMID: 29674694) further support the role of SOCS1 to have a function consistent with the immunodeficiency phenotype observed in patients via the regulation of JAK/STAT pathways.

In summary, there is definitive evidence supporting the relationship between SOCS1 in relation to autosomal dominant autoinflammatory syndrome with immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen PIRD GCEP on the meeting date February, 18, 2025 (SOP Version 11).