Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome
Journal of Clinical Immunology, 2026
Hamad S., Makhlouf M., Agrebi N., Kaddourah A., Abu-Hasan M., Al-Adba B., Sadoun A., Hubrack S., Aamer W., Segura M., Scialdone A., Machaca K., Saraiva L., Bout-Tabaku S., Lo B.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Purpose
ZNFX1 interferes with early viral replication after exposure to type I interferon, and interacts with mitochondrial antiviral sensors (MAVS) leading to a balanced expression of interferon-stimulated genes (ISGs). ZNFX1 deficiency mimics systemic autoinflammatory diseases and accurate identification may prevent early mortality. We compare a homozygous ZNFX1 frameshift mutation patient to subjects with known interferonopathies. We explore the association between this mutation, unregulated ISGs, and macrophage activation syndrome (MAS).
Methods
Study participants included our index patient, other patients with well-characterized interferonopathies, and healthy participants. We performed western blotting for ZNFX1 and whole Blood mRNA-seq, RT-qPCR, ELISA, and Olink Proteomics analysis to assess cytokine production and the underlying immune dysregulation.
Results
Our patient had elevated expression of interferon-inducible genes compared to healthy controls, but levels were comparable to subjects with known interferonopathies. Gene sequencing revealed a novel homozygous ZNFX1 frameshift variant resulting in a truncated protein. Transcriptomic analysis pointed to the top 3 cytokine upstream regulators, tumor necrosis factor (TNF), IL-1β, and interferon-gamma. ZNFX1 deficient patients appear to have a clinical profile that differs from classical type I interferonopathies, including features such as thrombotic microangiopathy (TMA) and a higher frequency of MAS.
Conclusions
ZNFX1 deficiency is an immune dysregulation disorder characterized by a robust type I interferon signature combined with elevated inflammatory cytokines, leading to severe early-onset multisystem inflammatory disease. Characterizing the immune profile allows targeted short-term treatments that may prolong life.