{
  "abstract": "OTOF gene dysfunction causes congenital deafness. OTOF gene therapy achieves promising clinical efficacy. However, OTOF variants of uncertain significance (VUS) hinder diagnosis and restrict eligibility for gene therapy in half of 135 hearing loss patients with biallelic OTOF variants in our cohort. Here, we establish a translational pipeline to reclassify VUSs and guide clinical decisions via functional analysis. We evaluate coding VUSs using an adeno-associated virus (AAV)-mediated variant delivery system into Otof−/− mice and evaluate non-coding VUSs via splicing assays. Isolated homozygous E1700Q confers normal hearing, while E1700Q consistently occurs in cis with K1992R in patients, and K1992R correlates with abnormal otoferlin subcellular localization. This pipeline reclassifies eight representative VUSs, enabling definitive molecular diagnoses for 38 patients. Seven eligible patients receive gene therapy and show auditory improvement, including one achieving near-normal hearing that was sustained for 1.5 years. This pipeline effectively expands the gene therapy eligibility for OTOF-related deafness. This study is registered with the Chinese Clinical Trial Registry: ChiCTR2200063181.",
  "abstract_shown": true,
  "affiliations": [
    "ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China",
    "Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China",
    "State Key Laboratory of Brain and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China",
    "NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China",
    "Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China",
    "Department of Otolaryngology-Head and Neck Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China",
    "Department of Otolaryngology, Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China",
    "Department of Otolaryngology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China",
    "The Reproduction Hospital of Guangxi Zhuang Autonomous Region, Nanning 530218, China",
    "International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China",
    "Department of Otorhinolaryngology–Head and Neck Surgery, Huadong Hospital, Fudan University, Shanghai 200233, China",
    "Institute of Medical Genetics and Genomics, Fudan University, Shanghai 200032, China",
    "Shanghai Academy of Natural Sciences (SANS), Shanghai 200031, China",
    "FuRong Laboratory, Changsha 410078, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 26,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3,
        4
      ],
      "name": "Liheng Chen"
    },
    {
      "affs": [
        1,
        2,
        3,
        4,
        5
      ],
      "name": "Min Yao"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4
      ],
      "name": "Honghai Tang"
    },
    {
      "affs": [
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        1,
        2,
        3,
        4
      ],
      "name": "Jingjing Zhao"
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    {
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        2,
        3,
        4
      ],
      "name": "Dan Mu"
    },
    {
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        4
      ],
      "name": "Daqi Wang"
    },
    {
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        3,
        4
      ],
      "name": "Sha Yu"
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    {
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        4
      ],
      "name": "Luo Guo"
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    {
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        4
      ],
      "name": "Qi Cao"
    },
    {
      "affs": [
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        2,
        3,
        4
      ],
      "name": "Luoying Jiang"
    },
    {
      "affs": [
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        3,
        4
      ],
      "name": "Chong Cui"
    },
    {
      "affs": [
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        3,
        4
      ],
      "name": "Lei Han"
    },
    {
      "affs": [
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        3,
        4
      ],
      "name": "Yuan Yuan"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4
      ],
      "name": "Shuang Han"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4
      ],
      "name": "Sen Zhang"
    },
    {
      "affs": [
        6
      ],
      "name": "Xiaoyi Gu"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4,
        7
      ],
      "name": "Yicheng Zeng"
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    {
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        3,
        4
      ],
      "name": "Bowen Zhang"
    },
    {
      "affs": [
        8
      ],
      "name": "Qi Zhao"
    },
    {
      "affs": [
        9
      ],
      "name": "Shuyuan Li"
    },
    {
      "affs": [
        9
      ],
      "name": "Yiyao Chen"
    },
    {
      "affs": [
        10
      ],
      "name": "Ru Zhang"
    },
    {
      "affs": [
        0,
        1,
        2,
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        4
      ],
      "name": "Huawei Li"
    },
    {
      "affs": [
        5
      ],
      "name": "Zhaoxin Ma"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4
      ],
      "name": "Geng-Lin Li"
    },
    {
      "affs": [
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        3,
        4,
        11,
        12,
        13
      ],
      "name": "Yilai Shu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e4gc0t5mmghfd.bib",
  "cited_by": 0,
  "doi": "10.1016/j.xcrm.2026.103093",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710384/",
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  "issns": [
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  "landing_url": "https://doi.org/10.1016/j.xcrm.2026.103093",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
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      "openalex",
      "2809|Hearing, Cochlea, Tinnitus, Genetics"
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  "pmcid": "PMC13710384",
  "pmid": "42843343",
  "published": "2026-10-07",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/e4gc0t5mmghfd.ris",
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      "origin": "openalex:2809|Hearing, Cochlea, Tinnitus, Genetics",
      "subfield": "neuroscience"
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  ],
  "title": "A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness",
  "title_text": "A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:22Z",
  "url": "https://research.draconitic.com/paper/e4gc0t5mmghfd",
  "venue": "Cell Reports Medicine",
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}