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Large-scale genetic profiling of hereditary ataxias in China: implications for a stepwise molecular diagnostic strategy.

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Τίτλος: Large-scale genetic profiling of hereditary ataxias in China: implications for a stepwise molecular diagnostic strategy.
Συγγραφείς: Yu JY; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.; Nanhu Brain-computer Interface Institute, Hangzhou, China., Sun YM; Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China., Dong Y; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Wu JJ; Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China., Zhu CH; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Du YC; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Zhang YX; Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China., Zhang Y; Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China., Zou SM; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Ma Y; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Dong HL; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. hailindong2015@zju.edu.cn.; Nanhu Brain-computer Interface Institute, Hangzhou, China. hailindong2015@zju.edu.cn., Wu ZY; Department of Medical Genetics and Center for Rare Diseases, and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. zhiyingwu@zju.edu.cn.; Nanhu Brain-computer Interface Institute, Hangzhou, China. zhiyingwu@zju.edu.cn.; MOE Frontier Science Center for Brain Science and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China. zhiyingwu@zju.edu.cn.
Πηγή: Translational neurodegeneration [Transl Neurodegener] 2026 Sep 29; Vol. 15 (1). Date of Electronic Publication: 2026 Sep 29.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: BioMed Central Country of Publication: England NLM ID: 101591861 Publication Model: Electronic Cited Medium: Print ISSN: 2047-9158 (Print) Linking ISSN: 20479158 NLM ISO Abbreviation: Transl Neurodegener Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : BioMed Central, 2012-
Ιατρικοί όροι (MeSH): Spinocerebellar Degenerations*/genetics , Spinocerebellar Degenerations*/diagnosis , Spinocerebellar Degenerations*/epidemiology , Genetic Testing*/methods , Genetic Profile*, China/epidemiology ; Molecular Diagnostic Techniques/methods ; Humans ; Retrospective Studies ; Female ; Male ; Cohort Studies ; Adult
Περίληψη: Background: Hereditary ataxias are clinically and genetically heterogeneous, which complicates clinical management, genetic counseling, and scientific research. Efficient molecular diagnosis is essential but requires molecular epidemiological considerations due to the variable genetic landscapes across regions and populations. In China, despite the established predominance of spinocerebellar ataxia type 3 (SCA3), comprehensive data on the genetic landscape of hereditary ataxias are limited and increasingly outdated, leaving insufficient evidence to support an epidemiology-informed molecular diagnostic strategy and its clinical implementation as a diagnostic algorithm.
Methods: We retrospectively established a large, real-world, comprehensive cohort of hereditary ataxias (the HARMONY cohort) recruited from two medical centers in the Yangtze River Delta region of China (2008-2024) for genetic profiling. Molecular diagnoses were categorized into four classifications ('Definitive', 'Probable', 'Unclear', 'Undiagnosed') by integrating previously identified causative variants with results from systematic genetic testing in etiologically undetermined probands, and the associated variants were mapped onto genetic landscapes.
Results: A total of 2096 probands were included in the HARMONY cohort, achieving a molecular diagnostic yield of 84.9%, with 1715 (81.8%) 'Definitive' and 65 (3.1%) 'Probable' positive diagnoses, alongside 87 (4.2%) 'Unclear' and 229 (10.9%) 'Undiagnosed' cases. While the genetic landscape was dominated by variants underlying SCA3 (1249; 59.6%), with SCA2 (150; 7.2%), SCA1 (139; 6.6%), SCA6 (51; 2.4%), putative SCA36 (36; 1.7%), and SCA12 (35; 1.7%) constituting the major subtypes, the genetic profiling revealed a long tail of rare genotypes. Onset age distributions were characterized for genotypes with ≥ 5 probands. No probands were found to carry expansions in ZFHX3, BEAN1, DAB1, THAP11, or FXN.
Conclusions: Genetic profiling of the HARMONY cohort revealed a skewed genetic landscape dominated by a few common repeat-expansion subtypes, alongside a markedly heterogeneous long tail of rare etiologies. The holistic profile supports a stepwise molecular diagnostic strategy, under which we propose a YRD (Yangtze River Delta)-oriented candidate diagnostic algorithm. This study provides an evidence base for early molecular diagnosis, prioritization of therapeutic development, and adaptive design of diagnostic tools for hereditary ataxias.
(© 2026. The Author(s).)
Competing Interests: Declarations. Ethics approval and consent to participate: The HARMONY study was approved by the Human Research Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine (approval No. 2025–1669), and the Ethics Committee of Huashan Hospital, Fudan University (approval No. 2025–1659). Written informed consent was obtained from all participants or their legal guardians. This study is registered with ClinicalTrials.gov (NCT07092358; registration date: July 29, 2025). Consent for publication: Not applicable. Competing interests: The authors report no potential conflicts of interest.
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Grant Information: 2025ZD0217702 Ministry of Science and Technology of China; 82230062 National Natural Science Foundation of China
Contributed Indexing: Keywords: Chinese population; Genetic landscape; Hereditary ataxias; Molecular diagnosis
Entry Date(s): Date Created: 20260929 Date Completed: 20260929 Latest Revision: 20261001
Update Code: 20261001
PubMed Central ID: PMC13621623
DOI: 10.1186/s40035-026-00584-y
PMID: 42806408
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2047-9158
DOI:10.1186/s40035-026-00584-y