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Peer-reviewedCC BY-NC-ND 4.0Cell Reports Medicine

A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness

  • Liheng Chen1,2,3,4,5
  • Min Yao2,3,4,5,6
  • Honghai Tang1,2,3,4,5
  • Jingjing Zhao1,2,3,4,5
  • Dan Mu1,2,3,4,5
  • Daqi Wang1,2,3,4,5
  • Sha Yu1,2,3,4,5
  • Luo Guo1,2,3,4,5
  • Qi Cao1,2,3,4,5
  • Luoying Jiang1,2,3,4,5
  • Chong Cui1,2,3,4,5
  • Lei Han1,2,3,4,5
14 more authors
  • Yuan Yuan1,2,3,4,5
  • Shuang Han1,2,3,4,5
  • Sen Zhang1,2,3,4,5
  • Xiaoyi Gu7
  • Yicheng Zeng1,2,3,4,5,8
  • Bowen Zhang1,2,3,4,5
  • Qi Zhao9
  • Shuyuan Li10
  • Yiyao Chen10
  • Ru Zhang11
  • Huawei Li1,2,3,4,5
  • Zhaoxin Ma6
  • Geng-Lin Li1,2,3,4,5
  • Yilai Shu1,2,3,4,5,12,13,14
14 affiliations
  1. 1ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China
  2. 2Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai 200031, China
  3. 3State Key Laboratory of Brain and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
  4. 4NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
  5. 5Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
  6. 6Department of Otolaryngology-Head and Neck Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
  7. 7Department of Otolaryngology, Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
  8. 8Department of Otolaryngology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China
  9. 9The Reproduction Hospital of Guangxi Zhuang Autonomous Region, Nanning 530218, China
  10. 10International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
  11. 11Department of Otorhinolaryngology–Head and Neck Surgery, Huadong Hospital, Fudan University, Shanghai 200233, China
  12. 12Institute of Medical Genetics and Genomics, Fudan University, Shanghai 200032, China
  13. 13Shanghai Academy of Natural Sciences (SANS), Shanghai 200031, China
  14. 14FuRong Laboratory, Changsha 410078, China
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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.

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Cite

BibTeXRIS
BibTeX
@article{chen2026translational,
  title = {{A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness}},
  author = {Liheng Chen and Min Yao and Honghai Tang and Jingjing Zhao and Dan Mu and Daqi Wang and Sha Yu and Luo Guo and Qi Cao and Luoying Jiang and Chong Cui and Lei Han and Yuan Yuan and Shuang Han and Sen Zhang and Xiaoyi Gu and Yicheng Zeng and Bowen Zhang and Qi Zhao and Shuyuan Li and Yiyao Chen and Ru Zhang and Huawei Li and Zhaoxin Ma and Geng-Lin Li and Yilai Shu},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = oct,
  doi = {10.1016/j.xcrm.2026.103093},
  url = {https://doi.org/10.1016/j.xcrm.2026.103093},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness
AU  - Liheng Chen
AU  - Min Yao
AU  - Honghai Tang
AU  - Jingjing Zhao
AU  - Dan Mu
AU  - Daqi Wang
AU  - Sha Yu
AU  - Luo Guo
AU  - Qi Cao
AU  - Luoying Jiang
AU  - Chong Cui
AU  - Lei Han
AU  - Yuan Yuan
AU  - Shuang Han
AU  - Sen Zhang
AU  - Xiaoyi Gu
AU  - Yicheng Zeng
AU  - Bowen Zhang
AU  - Qi Zhao
AU  - Shuyuan Li
AU  - Yiyao Chen
AU  - Ru Zhang
AU  - Huawei Li
AU  - Zhaoxin Ma
AU  - Geng-Lin Li
AU  - Yilai Shu
PY  - 2026
DA  - 2026/10/07
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103093
UR  - https://doi.org/10.1016/j.xcrm.2026.103093
AB  - 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.
SN  - 2666-3791
ER  -