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


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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Fig. 1: Refinement of a candidate region for BAFME.
Fig. 2: Identification of repeat-expansion mutations in SAMD12.
Fig. 3: Two repeat configurations of abnormal repeat expansions in SAMD12.
Fig. 4: Repeat length is inversely correlated with age at onset of epilepsy and shows intergenerational instability.
Fig. 5: Neuropathological study of patients with BAFME1.
Fig. 6: Identification of mutations in TTTCA- and TTTTA-repeat expansions in TNRC6A (BAFME6) and RAPGEF2 (BAFME7).


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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.

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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.

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Correspondence to Shoji Tsuji.

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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.

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Ishiura, H., Doi, K., Mitsui, J. et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet 50, 581–590 (2018). https://doi.org/10.1038/s41588-018-0067-2

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