Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

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Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

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We thank the patients and family members for participating in the study. We thank T. Sekiya (Department of Neurology, Sumitomo Hospital, Osaka, Japan), M. Kinoshita (Department of Neurology, Utano National Hospital, National Hospital Organization, Kyoto, Japan), M. Kanda (Department of Neurology, Ijinkai Takeda General Hospital, Kyoto, Japan), K. Hokkoku (Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan) and others for kindly collecting and providing clinical information, and K. Hirayama, Zhenghong Wu, M. Takeyama, K. Wakabayashi, N. Maruyama, T. Sugai, and Y. Tsukamoto for technical support. This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid (H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080) from the Ministry of Health, Welfare and Labour, Japan, and grants (15ek0109065h0002, 16kk0205001h0001, 17kk0205001h0002 and 17ek0109279h0001) from the Japan Agency for Medical Research and Development (AMED) to S.T. This work was also supported by KAKENHI (Grant-in-Aid for Young Scientists 17H05085) from the Japan Society for the Promotion of Science for H.I.

Author information

Author notes

  1. Deceased: Akira Ueki.


  1. Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan

    • Hiroyuki Ishiura
    • , Jun Mitsui
    • , Miho Kawabe Matsukawa
    • , Shota Shibata
    • , Aki Mitsue
    • , Masaki Tanaka
    • , Hidetoshi Date
    • , Takashi Matsukawa
    • , Junko Kanda
    • , Fumiko Kusunoki Nakamoto
    • , Jun Shimizu
    • , Toshihiro Hayashi
    • , Satomi Inomata-Terada
    • , Masashi Hamada
    • , Yuichiro Shirota
    • , Akatsuki Kubota
    •  & Shoji Tsuji
  2. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan

    • Koichiro Doi
    • , Jun Yoshimura
    • , Wei Qu
    • , Kazuki Ichikawa
    •  & Shinichi Morishita
  3. Advanced Genomics Center, National Institute of Genetics, Shizuoka, Japan

    • Asao Fujiyama
  4. Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

    • Yasuko Toyoshima
    • , Akiyoshi Kakita
    •  & Hitoshi Takahashi
  5. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan

    • Yutaka Suzuki
  6. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

    • Sumio Sugano
  7. Department of Laboratory Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan

    • Hideaki Yurino
  8. Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    • Koichiro Higasa
  9. Department of Neurology, Kyorin University, Tokyo, Japan

    • Yaeko Ichikawa
  10. Department of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan

    • Yuji Takahashi
  11. Department of Neurology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

    • Mana Higashihara
  12. Department of Neurology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    • Koji Abe
  13. Department of Neurology, Nishi-Niigata Chuo National Hospital, Niigata, Japan

    • Ryoko Koike
    •  & Yasuko Kuroha
  14. Department of Psychiatry, Toyosato Hospital, Ibaraki, Japan

    • Mutsuo Sasagawa
  15. Department of Epilepsy, Nishi-Niigata Chuo National Hospital, Niigata, Japan

    • Naoya Hasegawa
  16. Division of Cardiology, National Hospital Organization Takasaki General Medical Center, Gunma, Japan

    • Norio Kanesawa
  17. Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    • Takayuki Kondo
    •  & Takefumi Hitomi
  18. Department of Clinical Laboratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    • Takefumi Hitomi
  19. Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan

    • Masayoshi Tada
    •  & Osamu Onodera
  20. Department of Neurology, Tachikawa General Hospital, Niigata, Japan

    • Hiroki Takano
  21. Department of Neurology, Sannocho Hospital, Niigata, Japan

    • Yutaka Saito
  22. Department of Neurology, Sado General Hospital, Niigata, Japan

    • Kazuhiro Sanpei
  23. Department of Neurology, Niigata Medical Center, Niigata, Japan

    • Masatoyo Nishizawa
  24. Department of Psychiatry, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    • Masayuki Nakamura
    •  & Akira Sano
  25. Department of Neurology, Kurashikikinen Hospital, Okayama, Japan

    • Takeshi Yasuda
  26. Department of Neurology, Jichi Medical University, Saitama Medical Center, Saitama, Japan

    • Yoshio Sakiyama
  27. Department of Neurology, International University of Health and Welfare, Tochigi, Japan

    • Mieko Otsuka
  28. Third Department of Internal Medicine, National Defense Medical College, Saitama, Japan

    • Ken-ichi Kaida
  29. Department of Neurology, School of Medicine, Kitasato University, Kanagawa, Japan

    • Ritsuko Hanajima
  30. Department of Cell Physiology, School of Medicine, Kyorin University, Tokyo, Japan

    • Yasuo Terao
  31. Department of Neurology, Fukushima Medical University, Fukushima, Japan

    • Yoshikazu Ugawa
  32. Department of Neurology, University of Yamanashi, Yamanashi, Japan

    • Kishin Koh
    •  & Yoshihisa Takiyama
  33. Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan

    • Natsumi Ohsawa-Yoshida
    •  & Shoichi Ishiura
  34. Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan

    • Shoichi Ishiura
  35. Department of Neurology, Neurological Institute, Faculty of Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    • Ryo Yamasaki
  36. Department of Neurology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan

    • Akira Tamaoka
  37. Hiratsuka Hospital, Kanagawa, Japan

    • Hiroshi Akiyama
  38. Epilepsy Hospital Bethel Japan, Miyagi, Japan

    • Taisuke Otsuki
  39. Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    • Akio Ikeda
  40. Department of Neurology, International University of Health and Welfare Mita Hospital, Tokyo, Japan

    • Jun Goto
  41. Medical Genome Center, The University of Tokyo Hospital, Tokyo, Japan

    • Shoji Tsuji
  42. International University of Health and Welfare, Chiba, Japan

    • Shoji Tsuji


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H.I. and S.T. designed the study; H.I., J.M., M.K.M., A.F., Y. Toyoshima, A. Kakita, H. Takahashi, Y. Suzuki, S. Sugano, H.Y., S. Shibata, A.M., M. Tanaka, Y.I., Y. Takahashi, H.D., T.M., J.S., N.O.-Y., S.I., J.G., S.M. and S.T. performed the experiments and analyzed the data; H.I., K.D., J.Y., Y. Suzuki, W.Q., K.I., K.H., H.D. and S.M. performed computational analysis; H.I., M.K.M., Y. Toyoshima, A.K., H. Takahashi and S.T. performed neuropathological analyses; H.I., J.M., M.K.M., Y. Toyoshima, A.K., H. Takahashi, M. Tanaka, Y.I., Y. Takahashi, T.M., S. Shibata., J.K., F.K.N., M. Higashihara, K.A., R.K., M.S., Y.K., N.H., N.K., T.K., T. Hitomi, M. Tada, H. Takano, Y. Saito, K.S., O.O., M. Nishizawa, M. Nakamura, T.Y., Y. Sakiyama, M.O., A.U., K. Kaida, R.H., T. Hayashi, Y. Terao, S.I.-T., M. Hamada, Y. Shirota, A. Kubota, Y.U., K. Koh, Y. Takiyama, R.Y., A.T., H.A., T.O., A.S. and A.I. collected and analyzed clinical data and provided patients’ samples; and H.I., M.K.M., A. Kakita, S.M. and S.T. wrote the manuscript, together with contributions from all authors.

Competing interests

The authors declare no competing financial interests. A.I. currently belongs to The Department of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto University, which is an endowment department supported with a grant from GlaxoSmithKline K.K., NIHON KOHDEN CORPORATION, Otsuka Pharmaceuticals Co., and UCB Japan Co., Ltd., but there is no financial relationship to this work.

Corresponding author

Correspondence to Shoji Tsuji.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1-17, Supplementary Tables 1, 2, 4-10 and Supplementary Note

  2. Life Sciences Reporting Summary

  3. Supplementary Table 3

    Differentially expressed genes

  4. Supplementary Data

    Uncropped blot images