Article Text

Download PDFPDF
Original research
Long-read sequencing identified repeat expansions in the 5′UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease
  1. Jianwen Deng1,
  2. Muliang Gu1,
  3. Yu Miao2,
  4. Sheng Yao3,
  5. Min Zhu4,
  6. Pu Fang4,
  7. Xuefan Yu5,
  8. Pidong Li2,
  9. Yanan Su2,
  10. Jian Huang2,
  11. Jun Zhang6,
  12. Jiaxi Yu1,
  13. Fan Li1,
  14. Jing Bai1,
  15. Wei Sun1,
  16. Yining Huang1,
  17. Yun Yuan1,
  18. Daojun Hong4,6,
  19. Zhaoxia Wang1
  1. 1 Department of Neurology, Peking University First Hospital, Beijing, China
  2. 2 GrandOmics Biosciences, Beijing, China
  3. 3 Department of Neurology, Sixth Medical Center of PLA General Hospital, Beijing, China
  4. 4 Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang, China
  5. 5 Department of Neurology, Bethune First Affiliated Hospital of Jilin University, Nanchang, China
  6. 6 Department of Neurology, Peking University People's Hospital, Beijing, China
  1. Correspondence to Dr Daojun Hong, Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China; hongdaojun{at}; Dr Zhaoxia Wang, Department of Neurology, Peking University First Hospital, Beijing, China; drwangzx{at}


Background Neuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients.

Methods Fifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.

Results Our patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5′UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases.

Conclusion Our findings provided evidence that confirmed the GGC repeated expansion in the 5′UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.

  • genetics
  • neurology
  • NIID
  • GGC repeated expansion

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • JD and MG contributed equally.

  • Contributors DJH and ZXW conceived the research, designed studies and supervised the project; JWD, MLG and JXY designed and carried out experiments and analysed data; SY, MZ, PF, XFY, JZ, FL, JB, WS, YNH, YY, DJH and ZXW contributed to the clinical diagnosis and biopsy of NIID patients; YM, PDL, YNS and JH analysed the LRS data; JWD, DJH and ZXW wrote and edited the manuscript. All authors read and approved the final manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China under Grant No. 81460199, 81870996 and 81571219.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The research was approved by the ethics committee of Peking University First Hospital and Peking University People’s Hospital.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.