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Hamad, S.G.* ; Makhlouf, M.* ; Agrebi, N.* ; Kaddourah, A.* ; Abu-Hasan, M.* ; Al‐Adba, B.* ; Sadoun, A.* ; Hubrack, S.Z.* ; Aamer, W.* ; Ruiz Tejada Segura, M.L. ; Scialdone, A. ; Machaca, K.* ; Saraiva, L.R.* ; Bout-Tabaku, S.* ; Lo, B.*

Unraveling immune dysregulation in ZNFX1 deficiency: From interferonopathies to macrophage activation syndrome.

J. Clin. Immunol., DOI: 10.1007/s10875-026-02056-4 (2026)
Article in press DOI
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
PurposeZNFX1 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).MethodsStudy 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.ResultsOur 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.ConclusionsZNFX1 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Immune Dysregulation ; Immune System ; Frameshift Mutation ; Cytokine ; Tumor Necrosis Factor Alpha ; Transcriptome ; Macrophage ; Gene ; Interleukin 6
ISSN (print) / ISBN 0271-9142
e-ISSN 1573-2592
Journal Journal of Clinical Immunology
Publisher Springer
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Epigenetics and Stem Cells (IES)
Institiute of Functional Epigenetics (IFE)
Institute of Computational Biology (ICB)