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Long-read sequencing identified intronic repeat expansions in SAMD12 from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy
  1. Sheng Zeng1,
  2. Mei-yun Zhang2,
  3. Xue-jing Wang3,4,
  4. Zheng-mao Hu5,
  5. Jin-chen Li5,6,
  6. Nan Li1,
  7. Jun-ling Wang1,5,7,
  8. Fan Liang8,
  9. Qi Yang8,
  10. Qian Liu9,10,
  11. Li Fang9,10,
  12. Jun-wei Hao11,
  13. Fu-dong Shi11,
  14. Xue-bing Ding3,4,
  15. Jun-fang Teng3,4,
  16. Xiao-meng Yin1,4,
  17. Hong Jiang1,5,6,7,
  18. Wei-ping Liao12,
  19. Jing-yu Liu13,
  20. Kai Wang9,10,
  21. Kun Xia5,
  22. Bei-sha Tang1,5,6,7,14,15,16
  1. 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
  2. 2Department of Neurology, Tianjin Union Medical Center, Tianjin, China
  3. 3Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  4. 4Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Hunan, China
  5. 5Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
  6. 6National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan, China
  7. 7Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China
  8. 8GrandOmics Biosciences, Beijing, China
  9. 9Raymond G Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  10. 10Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  11. 11Department of Neurology, General Hospital, Tianjin Medical University, Tianjin, China
  12. 12Institute of Neuroscience, Department of Neurology of The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China
  13. 13Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China
  14. 14Parkinson’s Disease Center of Beijing Institute for Brain Disorders, Beijing, China
  15. 15Collaborative Innovation Center for Brain Science and China, Shanghai, China
  16. 16Collaborative Innovation Center for Genetics and Development, Shanghai, China
  1. Correspondence to Prof. Kai Wang, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA ; wangk{at}email.chop.edu, Prof. Kun Xia, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China ; xiakun48{at}163.com and Dr Bei-sha Tang, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; bstang7398{at}163.com

Abstract

Background The locus for familial cortical myoclonic tremor with epilepsy (FCMTE) has long been mapped to 8q24 in linkage studies, but the causative mutations remain unclear. Recently, expansions of intronic TTTCA and TTTTA repeat motifs within SAMD12 were found to be involved in the pathogenesis of FCMTE in Japanese pedigrees. We aim to identify the causative mutations of FCMTE in Chinese pedigrees.

Methods We performed genetic linkage analysis by microsatellite markers in a five-generation Chinese pedigree with 55 members. We also used array-comparative genomic hybridisation (CGH) and next-generation sequencing (NGS) technologies (whole-exome sequencing, capture region deep sequencing and whole-genome sequencing) to identify the causative mutations in the disease locus. Recently, we used low-coverage (~10×) long-read genome sequencing (LRS) on the PacBio Sequel and Oxford Nanopore platforms to identify the causative mutations, and used repeat-primed PCR for validation of the repeat expansions.

Results Linkage analysis mapped the disease locus to 8q23.3–24.23. Array-CGH and NGS failed to identify causative mutations in this locus. LRS identified the intronic TTTCA and TTTTA repeat expansions in SAMD12 as the causative mutations, thus corroborating the recently published results in Japanese pedigrees.

Conclusions We identified the pentanucleotide repeat expansion in SAMD12 as the causative mutation in Chinese FCMTE pedigrees. Our study also suggested that LRS is an effective tool for molecular diagnosis of genetic disorders, especially for neurological diseases that cannot be positively diagnosed by conventional clinical microarray and NGS technologies.

  • samd12
  • familial cortical myoclonic tremor with epilepsy
  • long read sequencing
  • repeat expansion

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Footnotes

  • KW, KX and B-sT contributed equally.

  • Contributors SZ performed the research, analysed the data and wrote the paper. M-yZ, J-wH, F-dS, X-jW, X-bD, J-fT, NL and X-mY provided the samples and assisted in clinical follow-up. Z-mH, J-cL, J-lW, FL, QY, QL and LF assisted in bioinformatics analysis. HJ, W-pL and J-yL supervised the study. KW, KX and B-sT designed the research, and provided financial and administrative support.

  • Funding This work was supported by the Program of National Natural Science Foundation of China (#81130021, #81430023 and #81300980).

  • Competing interests FL and QY are employees and KW is consultant of GrandOmics Biosciences.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Ethical Committee of Xiangya Hospital of Central South University in China (equivalent to an institutional review board).

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

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