Zeppieri M, Musa M, Cordeiro MF, Gagliano C, D’Esposito F. Reevaluating Usher syndrome: Transitioning from traditional subtypes to precision diagnosis. World J Med Genet 2025; 13(1): 112991 [DOI: 10.5496/wjmg.v13.i1.112991]
Corresponding Author of This Article
Marco Zeppieri, MD, PhD, Department of Ophthalmology, University Hospital of Udine, Maria Della Misericordia 15, Udine 33100, Italy. mark.zeppieri@asufc.sanita.fvg.it
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Ophthalmology
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Opinion Review
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Dec 2, 2025 (publication date) through Jan 20, 2026
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World Journal of Medical Genetics
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2220-3184
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Zeppieri M, Musa M, Cordeiro MF, Gagliano C, D’Esposito F. Reevaluating Usher syndrome: Transitioning from traditional subtypes to precision diagnosis. World J Med Genet 2025; 13(1): 112991 [DOI: 10.5496/wjmg.v13.i1.112991]
World J Med Genet. Dec 2, 2025; 13(1): 112991 Published online Dec 2, 2025. doi: 10.5496/wjmg.v13.i1.112991
Reevaluating Usher syndrome: Transitioning from traditional subtypes to precision diagnosis
Marco Zeppieri, Mutali Musa, Maria Francesca Cordeiro, Caterina Gagliano, Fabiana D’Esposito
Marco Zeppieri, Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
Marco Zeppieri, Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34129, Italy
Mutali Musa, Department of Optometry, University of Benin, Benin 300283, Nigeria
Maria Francesca Cordeiro, Fabiana D’Esposito, Imperial College Ophthalmic Research Group Unit, Imperial College, London NW1 5QH, United Kingdom
Caterina Gagliano, Fabiana D’Esposito, Department of Medicine and Surgery, University of Enna "Kore", Enna 94100, Italy
Caterina Gagliano, Eye Center, G.B. Morgagni-DSV, Catania 95125, Italy
Author contributions: Zeppieri M, Musa M, and Cordeiro MF contributed to the scientific editing; Zeppieri M and D’Esposito F did the research and writing of the manuscript; Cordeiro MF and Gagliano C assisted in the writing of the draft and final paper; Zeppieri M, Musa M, Cordeiro MF, Gagliano C, and D’Esposito F wrote the outline, were responsible for the conception and design of the study, assisted in the editing, making critical revisions of the manuscript and viewing all versions of the manuscript, provided the final approval of the article.
Conflict-of-interest statement: All authors have no conflicts of interest to declare.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Marco Zeppieri, MD, PhD, Department of Ophthalmology, University Hospital of Udine, Maria Della Misericordia 15, Udine 33100, Italy. mark.zeppieri@asufc.sanita.fvg.it
Received: August 12, 2025 Revised: August 14, 2025 Accepted: November 13, 2025 Published online: December 2, 2025 Processing time: 111 Days and 21.8 Hours
Abstract
Usher syndrome (USH) should no longer be considered a fixed diagnosis limited to syndromic early-onset sensorineural hearing loss and progressive vision decline due to rod-cone retinal dystrophy. Patients increasingly present with partial or delayed retinal manifestations, often lacking a clinically relevant audiological history. Concurrently, genomic testing uncovers variants that challenge the practical relevance of the traditional definition of type I, II, and III subclassifications. This review argues for a paradigm shift toward genotype-first diagnosis led by ophthalmologists, integrating retinal findings and audiological evaluations with comprehensive genetic information. The rise of gene-specific molecular therapies, including antisense oligonucleotides and CRISPR-mediated gene editing for USH2A and MYO7A, demands timely and accurate molecular categorization for each patient. Delays in precise molecular diagnosis may risk excluding patients from potentially vision-saving trials. Diagnostic gaps persist, including limited variant interpretation tools, underrepresentation of non-Caucasian populations in reference databases, and a lack of standardized retinal imaging protocols. The establishment of centralized, real-time Usher registries and interdisciplinary diagnostic models is essential. The future of USH management lies in anticipatory, individualized care that begins in the retina clinic.
Core Tip: Usher syndrome is a genetically and phenotypically heterogeneous disease that can no longer be approached with rigid subtype-based diagnostic criteria. This opinion review highlights the urgent need for genotype-first diagnostic pathways, identifies current limitations in variant interpretation and imaging standardization, and advocates for interdisciplinary care models. It also emphasizes how emerging gene therapies for USH2A, MYO7A, and CLRN1 necessitate early molecular diagnosis to ensure patient eligibility and optimal treatment outcomes.
