{
  "abstract": "Purpose\n\nZNFX1 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\n\nStudy 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\n\nOur 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\n\nZNFX1 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.",
    "Research Branch, Sidra Medicine, Doha, Qatar.",
    "Department of Pediatrics, Sidra Medicine, Doha, Qatar.",
    "Department of Pediatrics, Weill Cornell Medicine Qatar, Doha, Qatar.",
    "University of Qatar, Doha, Qatar.",
    "Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, Munich, Germany.",
    "Institute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, Germany.",
    "Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.",
    "Calcium Signaling Group, Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar.",
    "Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.",
    "College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.",
    "Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.",
    "Department of Pediatrics, Sidra Medicine, Doha, Qatar. sbouttabaku@sidra.org.",
    "Department of Pediatrics, Weill Cornell Medicine Qatar, Doha, Qatar. sbouttabaku@sidra.org.",
    "Research Branch, Sidra Medicine, Doha, Qatar. blo@sidra.org.",
    "College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar. blo@sidra.org."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sara G Hamad"
    },
    {
      "affs": [
        1
      ],
      "name": "Melanie Makhlouf"
    },
    {
      "affs": [
        1
      ],
      "name": "Nourhen Agrebi"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Ahmad Kaddourah"
    },
    {
      "affs": [
        2
      ],
      "name": "Mutasim Abu-Hasan"
    },
    {
      "affs": [
        2
      ],
      "name": "Buthaina Al-Adba"
    },
    {
      "affs": [
        1
      ],
      "name": "Ameera Sadoun"
    },
    {
      "affs": [
        1
      ],
      "name": "Satanay Z Hubrack"
    },
    {
      "affs": [
        1
      ],
      "name": "Waleed Aamer"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Mayra L Ruiz Tejada Segura"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Antonio Scialdone"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Khaled Machaca"
    },
    {
      "affs": [
        1,
        10,
        11
      ],
      "name": "Luis R Saraiva"
    },
    {
      "affs": [
        12,
        13
      ],
      "name": "Sharon Bout-Tabaku"
    },
    {
      "affs": [
        14,
        15
      ],
      "name": "Bernice Lo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4r02e4pggh7y6.bib",
  "cited_by": 0,
  "doi": "10.1007/s10875-026-02056-4",
  "fulltext_url": "https://europepmc.org/articles/PMC13727932",
  "id": "4r02e4pggh7y6",
  "issns": [
    "0271-9142",
    "1573-2592"
  ],
  "landing_url": "https://europepmc.org/article/MED/42972150",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7172537869",
  "pdf_url": "https://europepmc.org/articles/PMC13727932?pdf=render",
  "pmcid": "PMC13727932",
  "pmid": "42972150",
  "published": "2026-08-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4r02e4pggh7y6.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:49Z",
      "native_id": "MED:42972150",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42972150"
    },
    {
      "first_seen": "2026-11-06T12:23:43Z",
      "native_id": "PMC13727932",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s10875-026-02056-4"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|interferon and immune responses",
      "subfield": "immunology"
    }
  ],
  "title": "Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome.",
  "title_text": "Unraveling Immune Dysregulation in ZNFX1 Deficiency: From Interferonopathies to Macrophage Activation Syndrome.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:23:43Z",
  "url": "https://research.draconitic.com/paper/4r02e4pggh7y6",
  "venue": "Journal of clinical immunology",
  "versions": []
}