{
  "abstract": "Protein‐truncating variants in the 3′ region of a transcript, evading mRNA degradation and giving rise to aberrant truncated proteins, are an underrecognized cause in Mendelian diseases. Here, we report two individuals with heterozygous de novo nonsense variants in the penultimate and last exon of NUSAP1, both presenting with early‐onset refractory epilepsy, global developmental delay, congenital microcephaly, and a recognizable facial gestalt. RNA sequencing performed in one individual did not show a reduction in expression, compatible with escape of aberrant transcripts from nonsense mediated mRNA decay (NMD). We systematically analyzed gnomAD population data to delineate a critical region at the 3′ region of NUSAP1, where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls, while frameshift variants producing C‐terminal elongations appear tolerated. This position‐dependent model provides guidance for diagnostic variant interpretation.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Human Genetics, School of Medicine and Health, Technical University of Munich Munich Germany",
    "Medical Genetics Unit, Department of Mother and Child and Department of Medical Science Ferrara University Hospital and Ferrara University Ferrara Italy",
    "Laboratory of Medical Genetics, Papa Giovanni XXIII Hospital Bergamo Italy",
    "Institute of Neurogenomics, Helmholtz Zentrum München Munich Germany",
    "Department of Medical Sciences, Pediatric Section University Hospital of Ferrara Ferrara Italy",
    "Institute for Advanced Study, Technical University of Munich Garching Germany"
  ],
  "article_type": "brief report",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Maureen Jacob",
      "orcid": "0009-0002-6735-9205"
    },
    {
      "affs": [
        0
      ],
      "name": "Susann Badmann",
      "orcid": "0009-0003-4083-9230"
    },
    {
      "affs": [
        1
      ],
      "name": "Stefania Bigoni",
      "orcid": "0000-0003-0336-7097"
    },
    {
      "affs": [
        2
      ],
      "name": "Maria Iascone",
      "orcid": "0000-0002-4707-212X"
    },
    {
      "affs": [
        1
      ],
      "name": "Ilaria Vivaldi"
    },
    {
      "affs": [
        0
      ],
      "name": "Katharina Mayerhanser"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Robert Kopajtich",
      "orcid": "0000-0002-9119-3455"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Holger Prokisch",
      "orcid": "0000-0003-2379-6286"
    },
    {
      "affs": [
        4
      ],
      "name": "Cristina Forest"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Sebastian Eck"
    },
    {
      "affs": [
        0,
        3,
        5
      ],
      "name": "Michael Zech",
      "orcid": "0000-0001-8112-9153"
    },
    {
      "affs": [
        0
      ],
      "name": "Elisabeth Graf",
      "orcid": "0000-0002-1119-2285"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Matias Wagner",
      "orcid": "0000-0002-4454-8823"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Juliane Winkelmann",
      "orcid": "0000-0002-3074-599X"
    },
    {
      "affs": [
        0
      ],
      "name": "Theresa Brunet",
      "orcid": "0000-0002-5183-780X"
    },
    {
      "affs": [
        0
      ],
      "name": "Melanie Brugger",
      "orcid": "0000-0002-6920-8550"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dj3jxpmzaqx8e.bib",
  "cited_by": 0,
  "doi": "10.1111/cge.70244",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13728964/",
  "id": "dj3jxpmzaqx8e",
  "issns": [
    "0009-9163",
    "1399-0004"
  ],
  "landing_url": "https://doi.org/10.1111/cge.70244",
  "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",
      "Short Report"
    ],
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7211928710",
  "pdf_url": "https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cge.70244",
  "pmcid": "PMC13728964",
  "pmid": "42706591",
  "published": "2026-09-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dj3jxpmzaqx8e.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:21:48Z",
      "native_id": "PMC13728964",
      "source": "pmc",
      "url": "https://doi.org/10.1111/cge.70244"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genomics and Rare Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Pathogenicity of NUSAP1 Variants Is Defined by NMD‐Escape: Evidence From Two Novel Cases and Systematic Population‐Based Variant Analysis",
  "title_text": "Pathogenicity of NUSAP1 Variants Is Defined by NMD‐Escape: Evidence From Two Novel Cases and Systematic Population‐Based Variant Analysis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:21:48Z",
  "url": "https://research.draconitic.com/paper/dj3jxpmzaqx8e",
  "venue": "Clinical Genetics",
  "versions": []
}