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Original research
Clinical and genetic analysis of familial neuromyelitis optica spectrum disorder in Chinese: associated with ubiquitin-specific peptidase USP18 gene variants
  1. Yanyu Chang1,
  2. Luyao Zhou1,
  3. Xiaonan Zhong1,
  4. Ziyan Shi2,
  5. Xiaobo Sun1,
  6. Yuge Wang1,
  7. Rui Li1,
  8. Youming Long3,
  9. Hongyu Zhou2,
  10. Chao Quan4,
  11. Allan G Kermode1,5,
  12. Qingfen Yu1,
  13. Wei Qiu1
  1. 1Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
  2. 2Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  3. 3Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
  4. 4Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
  5. 5Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia, Australia
  1. Correspondence to Professor Wei Qiu, Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; qiuwei{at}mail.sysu.edu.cn; Dr. Qingfen Yu, Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; yuqf5{at}mail.sysu.edu.cn

Abstract

Background Familial clustering of neuromyelitis optica spectrum disorder (NMOSD) was present in Chinese. This study was to investigate the clinical characteristics and genetic background of familial NMOSD.

Methods Through questionnaires in four medical centres in 2016–2020, we identified 10 families with NMOSD aggregation. The statistical differences of clinical characteristics between familial and sporadic NMOSD (22 cases and 459 cases) were summarised. The whole-exome sequencing (WES) for seven families (13 cases and 13 controls) was analysed, compared with our previous WES data for sporadic NMOSD (228 cases and 1 400 controls). The family-based and population-based association and linkage analysis were conducted to identify the pathogenetic genes, the variant impacts were predicted.

Results The familial occurrence was 0.87% in Chinese. Familial patients had higher expanded disability status scale score than sporadic patients (p=0.03). The single-nucleotide polymorphism (SNP) rs2252257 in the promoter and enhancer of ubiquitin-specific peptidase USP18 was linked to familial NMOSD (p=7.8E-05, logarithm of the odds (LOD)=3.1), SNPs rs361553, rs2252257 and rs5746523 were related to sporadic NMOSD (p=1.29E-10, 3.45E-07 and 2.01E-09, respectively). Patients with the SNP rs361553 T/T genotype had higher recurrence rate than C/T or C/C genotype (1.22±0.85 vs 0.69±0.57 and 0.81±0.65, p=0.003 and 0.001, respectively). SNPs rs361553 and rs2252257 altered USP18 expression in brain and nerve tissues.

Conclusion Most clinical characteristics of familial NMOSD were indistinguishable from sporadic NMOSD except for the worst episodes severity. USP18 with impaired intronic regulatory function contributed to the pathogenesis of NMOSD.

  • neuroimmunology
  • genetics
  • multiple sclerosis

Data availability statement

Data are available upon reasonable request. The deidentified clinical and genetic data that support the findings of the study are available from the corresponding authors, Dr. Wei Qiu (qiuwei@mail.sysu.edu.cn) and Dr. Qingfen Yu (yuqf5@mail.sysu.edu.cn), upon reasonable request. There is no additional information available.

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Data availability statement

Data are available upon reasonable request. The deidentified clinical and genetic data that support the findings of the study are available from the corresponding authors, Dr. Wei Qiu (qiuwei@mail.sysu.edu.cn) and Dr. Qingfen Yu (yuqf5@mail.sysu.edu.cn), upon reasonable request. There is no additional information available.

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Footnotes

  • YC and LZ contributed equally.

  • QY and WQ contributed equally.

  • Contributors Guarantor:WQ; Conceptualisation: WQ, AGK; data curation: YC, XS; formal analysis: QY, YC; investigation: LZ, XZ, ZS, YW, RL, HZ, YL, CQ; methodology: WQ, QY; software: QY; visualisation: YC; writing - original draft: QY, YC; writing - review and editing: WQ, QY.

  • Funding This work was supported by grants from the National Natural Science Foundation of China (#81771300, #81971140) and the Natural Science Foundation of Guangdong Province (#2020A1515110795, #2020A1515010053).

  • 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.