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Peer-reviewedCC BYJournal of clinical immunology

Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome.

  • Sara G Hamad1
  • Melanie Makhlouf2
  • Nourhen Agrebi2
  • Ahmad Kaddourah3,4,5
  • Mutasim Abu-Hasan3
  • Buthaina Al-Adba3
  • Ameera Sadoun2
  • Satanay Z Hubrack2
  • Waleed Aamer2
  • Mayra L Ruiz Tejada Segura6,7,8
  • Antonio Scialdone6,7,8
  • Khaled Machaca9,10
3 more authors
  • Luis R Saraiva2,11,12
  • Sharon Bout-Tabaku13,14
  • Bernice Lo15,16
16 affiliations
  1. 1Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
  2. 2Research Branch, Sidra Medicine, Doha, Qatar.
  3. 3Department of Pediatrics, Sidra Medicine, Doha, Qatar.
  4. 4Department of Pediatrics, Weill Cornell Medicine Qatar, Doha, Qatar.
  5. 5University of Qatar, Doha, Qatar.
  6. 6Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, Munich, Germany.
  7. 7Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany.
  8. 8Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
  9. 9Calcium Signaling Group, Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar.
  10. 10Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
  11. 11College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
  12. 12Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
  13. 13Department of Pediatrics, Sidra Medicine, Doha, Qatar. [email protected].
  14. 14Department of Pediatrics, Weill Cornell Medicine Qatar, Doha, Qatar. [email protected].
  15. 15Research Branch, Sidra Medicine, Doha, Qatar. [email protected].
  16. 16College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar. [email protected].
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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.

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Cite

BibTeXRIS
BibTeX
@article{hamad2026unraveling,
  title = {{Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome.}},
  author = {Sara G Hamad and Melanie Makhlouf and Nourhen Agrebi and Ahmad Kaddourah and Mutasim Abu-Hasan and Buthaina Al-Adba and Ameera Sadoun and Satanay Z Hubrack and Waleed Aamer and Mayra L Ruiz Tejada Segura and Antonio Scialdone and Khaled Machaca and Luis R Saraiva and Sharon Bout-Tabaku and Bernice Lo},
  journal = {Journal of clinical immunology},
  year = {2026},
  month = aug,
  doi = {10.1007/s10875-026-02056-4},
  url = {https://europepmc.org/article/MED/42972150},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome.
AU  - Sara G Hamad
AU  - Melanie Makhlouf
AU  - Nourhen Agrebi
AU  - Ahmad Kaddourah
AU  - Mutasim Abu-Hasan
AU  - Buthaina Al-Adba
AU  - Ameera Sadoun
AU  - Satanay Z Hubrack
AU  - Waleed Aamer
AU  - Mayra L Ruiz Tejada Segura
AU  - Antonio Scialdone
AU  - Khaled Machaca
AU  - Luis R Saraiva
AU  - Sharon Bout-Tabaku
AU  - Bernice Lo
PY  - 2026
DA  - 2026/08/06
JO  - Journal of clinical immunology
DO  - 10.1007/s10875-026-02056-4
UR  - https://europepmc.org/article/MED/42972150
AB  - 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.
SN  - 0271-9142
SN  - 1573-2592
ER  -