Evidence map›Paper›PMID 42806408›Full record

ArticleTranslational neurodegeneration2026

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

Jin-Yang Yu, Yi-Min Sun, Yi Dong, Jian-Jun Wu, Chen-Hao Zhu, Yi-Chu Du, Yi-Xin Zhang, Yue Zhang, Sheng-Mei Zou, Yin Ma and 2 more

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Article in Translational neurodegeneration, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

12 authors.

Jin-Yang Yu *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.
Yi-Min Sun *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.
Yi Dong *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.
Jian-Jun Wu *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.
Chen-Hao ZhuDepartment 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.
Yi-Chu DuDepartment 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.
Yi-Xin ZhangDepartment 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.
Yue ZhangDepartment 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.
Sheng-Mei ZouDepartment 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.
Yin MaDepartment 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.
Hai-Lin DongDepartment 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.
Zhi-Ying WuDepartment 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.ORCID https://orcid.org/0000-0003-2106-572X

Funding

Ministry of Science and Technology of China 2025ZD0217702National Natural Science Foundation of China 82230062
6 · The paper itself

Abstract

backgroundHereditary 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.

methodsWe 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.

resultsA 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.

conclusionsGenetic 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.

Indexed as

Genetic ProfileGenetic TestingSpinocerebellar DegenerationsAdultChinaCohort StudiesFemaleHumansMaleMolecular Diagnostic TechniquesRetrospective StudiesChinese populationGenetic landscapeHereditary ataxiasMolecular diagnosis

Identifiers

PMID42806408
PMCPMC13621623

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