{
  "abstract": "PurposeChildren with suspected rare genetic disorders often remain undiagnosed after exome, gene panel, or chromosomal microarray testing. We sought to define recurrent missed-diagnosis mechanisms and evaluate an integrated clinical-genomic reanalysis framework.\n\nMethodsWe studied 75 participants with rare or striking pediatric-onset phenotypes who remained undiagnosed after prior genetic testing. Trio genome sequencing evaluated SNVs, indels and copy-number variants. RNA sequencing was performed in 63 participants to assess aberrant expression and splicing, with targeted follow-up assays used selectively for prioritized variants. Clinician-genome scientist review integrated longitudinal phenotyping, physician input, and inheritance. Unresolved cases underwent research-level candidate prioritization.\n\nResultsClinically reportable findings were returned in 9, including two with multilocus findings: 5 explained the primary phenotype and 4, while not fully explanatory, were clinically relevant and informing surveillance, management, or family follow-up. Previously missed findings reflected technical limitations, including deep intronic splice-altering variants supported by transcriptome analysis and a genomic deletion, and interpretive limitations related to incomplete phenotype integration or narrowly scoped prior testing. Research-level analysis prioritized six candidate genes, including biallelic ACHE variants with reduced enzymatic activity.\n\nConclusionIntegrated clinical-genomic reanalysis framework identified diagnostic gaps, recovered care-informing findings, and prioritized candidate genes for rare disease discovery.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 25,
  "authors": [
    {
      "name": "H. Gu"
    },
    {
      "name": "A. Sabo"
    },
    {
      "name": "S. V. Jangam"
    },
    {
      "name": "H. Hashimoto"
    },
    {
      "name": "C. Y. Miyake"
    },
    {
      "name": "B. Yuan"
    },
    {
      "name": "C. Gijavanekar"
    },
    {
      "name": "E. Venner"
    },
    {
      "name": "V. Korchina"
    },
    {
      "name": "S. H. Elsea"
    },
    {
      "name": "D. M. Muzny"
    },
    {
      "name": "E. Mizerik"
    },
    {
      "name": "B. Vuocolo"
    },
    {
      "name": "P. Srivaths"
    },
    {
      "name": "L. F. Satter"
    },
    {
      "name": "S. Ochoa"
    },
    {
      "name": "S. Sisley"
    },
    {
      "name": "P. B. Mihindou"
    },
    {
      "name": "O. Kanca"
    },
    {
      "name": "S. Yamamoto"
    },
    {
      "name": "Z. Liu"
    },
    {
      "name": "M. F. Wangler"
    },
    {
      "name": "R. A. Gibbs"
    },
    {
      "name": "H. J. Bellen"
    },
    {
      "affs": [
        0
      ],
      "name": "K. Y. King"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dqt8jr0h428ee.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.24.26363679",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363679v1.full",
  "id": "dqt8jr0h428ee",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363679v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7214886273",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363679v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dqt8jr0h428ee.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:45Z",
      "native_id": "10.64898/2026.09.24.26363679",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363679v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort",
  "title_text": "Integrated Clinical-Genomic Reanalysis Identifies Diagnostic Gaps and Candidate Genes in a Pediatric Rare Disease Cohort",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:45Z",
  "url": "https://research.draconitic.com/paper/dqt8jr0h428ee",
  "venue": "medRxiv",
  "versions": []
}