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A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing

Journal of Human Genetics (2019) | Download Citation


We report a family with progressive myoclonic epilepsy who underwent whole-exome sequencing but was negative for pathogenic variants. Similar clinical courses of a devastating neurodegenerative phenotype of two affected siblings were highly suggestive of a genetic etiology, which indicates that the survey of genetic variation by whole-exome sequencing was not comprehensive. To investigate the presence of a variant that remained unrecognized by standard genetic testing, PacBio long-read sequencing was performed. Structural variant (SV) detection using low-coverage (6×) whole-genome sequencing called 17,165 SVs (7,216 deletions and 9,949 insertions). Our SV selection narrowed down potential candidates to only five SVs (two deletions and three insertions) on the genes tagged with autosomal recessive phenotypes. Among them, a 12.4-kb deletion involving the CLN6 gene was the top candidate because its homozygous abnormalities cause neuronal ceroid lipofuscinosis. This deletion included the initiation codon and was found in a GC-rich region containing multiple repetitive elements. These results indicate the presence of a causal variant in a difficult-to-sequence region and suggest that such variants that remain enigmatic after the application of current whole-exome sequencing technology could be uncovered by unbiased application of long-read whole-genome sequencing.

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We would like to thank all the subjects for participating in this study. We also thank N. Watanabe, T. Miyama, M. Sato, and K. Takabe for their technical assistance. We are also grateful to Edanz ( for editing the English text of a draft of this manuscript. This work was supported by AMED under grant numbers JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18km045205, and JP18kk020500; JSPS KAKENHI under grant numbers JP17K15630, JP17H01539, JP17K10080, and JP17K15630; the Ministry of Health, Labour, and Welfare; and Takeda Science Foundation.

Author information


  1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan

    • Takeshi Mizuguchi
    • , Satoko Miyatake
    • , Noriko Miyake
    •  & Naomichi Matsumoto
  2. Division of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, Kasugai, Aichi, 480-0392, Japan

    • Takeshi Suzuki
    • , Chihiro Abe
    •  & Ayako Umemura
  3. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan

    • Katsushi Tokunaga
    •  & Yosuke Kawai
  4. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, 856-8562, Japan

    • Minoru Nakamura
  5. Division of Biomedical Information Analysis, Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan

    • Masao Nagasaki
  6. Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan

    • Kengo Kinoshita
    •  & Yasunobu Okamura
  7. Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, 980-8573, Japan

    • Kengo Kinoshita
    •  & Yasunobu Okamura
  8. Graduate School of Information Sciences, Tohoku University, Sendai, 980-8579, Japan

    • Kengo Kinoshita
  9. Clinical Genetics Department, Yokohama City University Hospital, Yokohama, 236-0004, Japan

    • Satoko Miyatake


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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Naomichi Matsumoto.

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