{
  "abstract": "Background: The role of small extracellular vesicles (sEVs), such as exosomes, in cell-to-cell communication is increasingly recognized. Both during development and postnatally, sEVs have been shown to mediate a multitude of essential functions in the central nervous system. While abnormal sEV biogenesis has been observed in a number of neurodevelopmental disorders, a causal link has been largely lacking.\n\nMethods: We clinically evaluated five families in which newborns presented with a novel neonatal-onset encephalopathy. Positional mapping, exome sequencing, and trio exome sequencing were utilized to identify the underlying genetic variants. Additionally, we utilized Vps25 hypomorphic mouse mutants and performed cellular assays to evaluate ESCRT-II interaction, cellular localization, and sEV secretion and cargo capacities.\n\nResults: The observed lethal encephalopathy is characterized by severe hypotonia, brain anomalies, and epilepsy. In families 1, 4, and 5 (multiplex consanguineous), we identified a novel homozygous missense variant in VPS25 as the likely candidate. Family 2 comprises a simplex case with two missense variants in trans in VPS25, one of which impacts the same residue as in the other three families. Family 3 also comprises a simplex case where we revealed a homozygous missense variant. VPS25 is an essential component of ESCRT-II, itself required for sEV biogenesis. We show that Vps25 hypomorphic mouse mutants recapitulate the developmental brain malformation observed in patients. We also show that mutant VPS25 is associated with abnormal ESCRT-II interaction, abnormal cellular localization, and highly abnormal sEVs. Specifically, mutant cells displayed engorged multivesicular bodies and were significantly defective in their capacity to secrete sEVs such as exosomes, while secreted sEVs contained altered cargo, lacking vital proteins for axon protection and maintenance.\n\nConclusions: We report a novel neurodevelopmental disorder caused by biallelic hypomorphic variants in VPS25. The consistent impact of these variants on sEV biogenesis suggests a potential pathomechanism. While future cases will further delineate the phenotypic spectrum, these findings offer a new perspective on abnormal sEVs as drivers of human neurodevelopmental disorders.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13073-026-01693-z.",
  "abstract_shown": true,
  "affiliations": [
    "Biomedical Sciences Division, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900 Saudi Arabia",
    "Department of Translational Genomics, Genomic Medicine Centre of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia",
    "Program in Craniofacial Biology, Department of Orofacial Sciences, Department of Anatomy, Institute for Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA USA",
    "Institute of Human Genetics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, 5020 Austria",
    "KAUST Core Labs, KAUST, Thuwal, 23955-6900 Kingdom of Saudi Arabia",
    "Lifera Omics, Lifera Omics Innovation Boulevard St, KAFD, Al Aqeeq Dist., Riyadh, 13519 Saudi Arabia",
    "Division of Neonatology, Department of Pediatrics and Adolescent Medicine, Paracelsus Medical University, Salzburg, 5020 Austria",
    "Wellness and Preventative Medicine Institute, Health Sector, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442 Saudi Arabia",
    "Department of Obstetrics and Gynecology, Paracelsus Medical University, Salzburg, 5020 Austria",
    "Department of Pediatrics, and Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, St. Louis, MO USA",
    "Department of Pediatrics, Saint Louis University School of Medicine, St Louis, MO USA",
    "Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia",
    "Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia",
    "Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia",
    "Department of Pediatrics, King Fahad Hospital of the University, Al-Khobar, Saudi Arabia",
    "Institute of Human Genetics, University of Regensburg, Regensburg, 93053 Germany",
    "Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, 93053 Germany",
    "Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD USA",
    "Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD USA",
    "College of Medicine, Alfaisal University, Riyadh, Saudi Arabia",
    "KAUST Center of Excellence for Smart Health (KCSH), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 37,
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    {
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        0
      ],
      "name": "Ioannis Isaioglou"
    },
    {
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        1
      ],
      "name": "Lama AlAbdi"
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        0
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      "name": "Muhammad Tehseen"
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        0
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      "name": "Yossef Lopez de los Santos"
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        0
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      "name": "Mansour Aldehaiman"
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    {
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        0
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      "name": "Gloria Lopez-Madrigal"
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        1
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      "name": "Norah Altuwaijri"
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        2
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      "name": "Viviana Hermosilla Aguayo"
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    {
      "affs": [
        3
      ],
      "name": "Anna Pleyers"
    },
    {
      "affs": [
        4
      ],
      "name": "Maya Ayach"
    },
    {
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        4
      ],
      "name": "Ashraf Al-Amoudi"
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    {
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        0
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      "name": "Jing Kai"
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      "name": "Vlad-Stefan Raducanu"
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        5
      ],
      "name": "Bader Alhaddad"
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        6
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      "name": "Edda Hofstätter"
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        0
      ],
      "name": "Amani Al-Amodi"
    },
    {
      "affs": [
        1
      ],
      "name": "Mais O. Hashem"
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    {
      "affs": [
        7
      ],
      "name": "Hessa S. Alsaif"
    },
    {
      "affs": [
        8
      ],
      "name": "Claudius Fazelnia"
    },
    {
      "affs": [
        1
      ],
      "name": "Firdous Abdulwahab"
    },
    {
      "affs": [
        1
      ],
      "name": "Amal Jaafar"
    },
    {
      "affs": [
        1
      ],
      "name": "Tarfa Alshidi"
    },
    {
      "affs": [
        1
      ],
      "name": "Rana Helaby"
    },
    {
      "affs": [
        9
      ],
      "name": "Adriana M. Montaño"
    },
    {
      "affs": [
        10
      ],
      "name": "Kara C. Klemp"
    },
    {
      "affs": [
        10
      ],
      "name": "Ellen Totten"
    },
    {
      "affs": [
        11
      ],
      "name": "Wesam Kurdi"
    },
    {
      "affs": [
        12
      ],
      "name": "Saly Eltohamy"
    },
    {
      "affs": [
        13
      ],
      "name": "Hadeel Abdollah E. Alrukban"
    },
    {
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        14
      ],
      "name": "Bashayer Alawam"
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    {
      "affs": [
        2
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      "name": "Licia Selleri"
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    {
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        15,
        16
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      "name": "Davor Lessel"
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    {
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        17,
        18
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      "name": "Dimitrios Kapogiannis"
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    {
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      "name": "Samir M. Hamdan"
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        10
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      "name": "Stephen R. Braddock"
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    {
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        0,
        1,
        5,
        19
      ],
      "name": "Fowzan S. Alkuraya"
    },
    {
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        0,
        20
      ],
      "name": "Jasmeen S. Merzaban"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e4adgperh11d1.bib",
  "cited_by": 0,
  "doi": "10.1186/s13073-026-01693-z",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712088/",
  "id": "e4adgperh11d1",
  "issns": [
    "1756-994X"
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  "landing_url": "https://doi.org/10.1186/s13073-026-01693-z",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "1312|Extracellular vesicles in disease"
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  "openalex": "W7223666878",
  "pdf_url": null,
  "pmcid": "PMC13712088",
  "pmid": "42934717",
  "published": "2026-09-14",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/e4adgperh11d1.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:44Z",
      "native_id": "PMC13712088",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s13073-026-01693-z"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Extracellular vesicles in disease",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy",
  "title_text": "Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:44Z",
  "url": "https://research.draconitic.com/paper/e4adgperh11d1",
  "venue": "Genome Medicine",
  "versions": []
}