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Genotype-phenotype correlations
Original research
Novel variants and genotype-phenotype correlation in a multicentre cohort of GNE myopathy in China
  1. Kexin Jiao1,
  2. Jialong Zhang1,
  3. Qiuxiang Li2,
  4. Xiaoqing Lv3,
  5. Yanyan Yu4,
  6. Bochen Zhu1,
  7. Huahua Zhong1,
  8. Xu’en Yu5,
  9. Jia Song6,
  10. Qing Ke7,
  11. Fangyuan Qian8,
  12. Xinghua Luan9,
  13. Xiaojie Zhang9,
  14. Xueli Chang10,
  15. Liang Wang11,
  16. Meirong Liu12,
  17. Jihong Dong13,
  18. Zhangyu Zou14,
  19. Bitao Bu15,
  20. Haishan Jiang16,
  21. LingChun Liu17,
  22. Yue Li15,
  23. Dongyue Yue18,
  24. Xuechun Chang19,
  25. Yongsheng Zheng1,
  26. Ningning Wang1,
  27. Mingshi Gao20,
  28. Xingyu Xia1,
  29. Nachuan Cheng1,
  30. Tao Wang21,22,
  31. Su-Shan Luo1,
  32. Jianying Xi1,
  33. Jie Lin1,
  34. Jiahong Lu1,
  35. Chongbo Zhao1,
  36. Huan Yang2,
  37. Pengfei Lin3,
  38. Daojun Hong4,
  39. Zhe Zhao23,
  40. Zhiqiang Wang24,
  41. Wenhua Zhu1
  1. 1Department of Neurology, Huashan Hospital Fudan University, Shanghai, Shanghai, China
  2. 2Department of Neurology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, China
  3. 3Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China
  4. 4Department of Neurology and Department of Medical Genetics, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
  5. 5Department of Neurology, The Affiliated Hospital of Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
  6. 6Department of Neurology, Henan Provincial People's Hospital, Zhengzhou, Henan, China
  7. 7Department of Neurology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  8. 8Department of Neurology, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
  9. 9Department of Neurology, Shanghai Sixth People's Hospital, Shanghai, China
  10. 10Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
  11. 11Department of Neurology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
  12. 12Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
  13. 13Department of Neurology, Zhongshan Hospital Fudan University, Shanghai, Shanghai, China
  14. 14Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
  15. 15Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  16. 16Department of Neurology, Southern Medical University Nanfang Hospital, Guangzhou, China, China
  17. 17Department of Neurology, First People's Hospital of Yunnan, Kunming, Yunnan, China
  18. 18Department of Neurology, Jing'an District Centre Hospital of Shanghai, Shanghai, Shanghai, China
  19. 19Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
  20. 20Department of Pathology, Huashan Hospital Fudan University, Shanghai, Shanghai, China
  21. 21Department of Anesthesiology, Zhongshan hospital, Shanghai, China
  22. 22Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science,Fudan University, Shanghai, China
  23. 23Department of Neuromuscular Disease, Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
  24. 24The Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Xiamen, Fujian, China
  1. Correspondence to Dr Wenhua Zhu; whzhu{at}fudan.edu.cn; Dr Zhiqiang Wang; fmuwzq{at}fjmu.edu.cn; Dr Zhe Zhao; vanilla78{at}sina.com; Dr Daojun Hong; hongdaojun{at}hotmail.com

Abstract

Background GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway.

Objective This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations.

Methods We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity.

Results This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients.

Conclusions Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.

  • neuromuscular diseases
  • genotype
  • genetic variation

Data availability statement

Data are available on reasonable request. The original contributions presented in the study are included in the article/online supplemental material. Further inquiries can be directed to the corresponding authors.

https://doi.org/10.1136/jmg-2024-110149

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    Data availability statement

    Data are available on reasonable request. The original contributions presented in the study are included in the article/online supplemental material. Further inquiries can be directed to the corresponding authors.

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    Footnotes

    • X @Sushan Luo

    • KJ, JZ, QL and XLv contributed equally.

    • Contributors KJ and JZ drafted the manuscript and analysed the data. QL and Xlu designed and carried out LRS and RP-PCR, and analysed data. DH supervised the molecular analysis and created the figures. QK provided technical support for electrophysiological diagnosis. DY analysed muscle imaging and provided technical assistance for muscle pathology. MG provided technical assistance for muscle pathology. CZ verified and interpreted the clinical, pathological and molecular results. JD, ZZ, JS, FQ, XLv, XZ, XChang, LW, ML, BB, HJ, LCL, YL, DY, XC, NW, XX, NC, TW, S-SL, JX, JL, JHL, HZ, YY, BZ, PL, YZ and HY contributed to case diagnosis and acquisition of clinical data. WZ revised the manuscript and supervised the project. JX drafted and revised the manuscript, and designed and supervised the project. ZW designed and conceptualised the study, revised the manuscript and supervised the project. All authors have participated sufficiently in the work and approved the final version of the manuscript for submission. Guarantor for the study: WZ.

    • Funding WZ and JX were supported by Clinical Research Project Supported by Huashan Hospital, Fudan University; National Natural Science Foundation of China (82171398, 82271437) and Fudan University Brain Science Interdisciplinary Integration Exploration Project (YN-013).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.