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Original research
Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese
  1. Satoko Miyatake1,2,
  2. Hiroshi Doi3,
  3. Hiroaki Yaguchi4,
  4. Eriko Koshimizu1,
  5. Naoki Kihara5,
  6. Tomoyasu Matsubara5,
  7. Yasuko Mori6,
  8. Kenjiro Kunieda6,
  9. Yusaku Shimizu7,
  10. Tomoko Toyota8,
  11. Shinichi Shirai4,
  12. Masaaki Matsushima4,
  13. Masaki Okubo3,
  14. Taishi Wada3,
  15. Misako Kunii3,
  16. Ken Johkura9,
  17. Ryosuke Miyamoto5,
  18. Yusuke Osaki5,
  19. Takabumi Miyama1,
  20. Mai Satoh1,
  21. Atsushi Fujita1,
  22. Yuri Uchiyama1,10,
  23. Naomi Tsuchida1,10,
  24. Kazuharu Misawa1,11,
  25. Kohei Hamanaka1,12,
  26. Haruka Hamanoue2,
  27. Takeshi Mizuguchi1,
  28. Hiroyuki Morino13,
  29. Yuishin Izumi5,
  30. Takayoshi Shimohata6,
  31. Kunihiro Yoshida14,15,
  32. Hiroaki Adachi8,
  33. Fumiaki Tanaka3,
  34. Ichiro Yabe4,
  35. Naomichi Matsumoto1,2,10
  1. 1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  2. 2Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan
  3. 3Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  4. 4Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
  5. 5Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  6. 6Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan
  7. 7Department of Neurology, Ina Central Hospital, Ina, Japan
  8. 8Department of Neurology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan
  9. 9Department of Neurology, Yokohama Brain and Spine Center, Yokohama, Japan
  10. 10Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan
  11. 11RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
  12. 12Institute for the Advanced Study of Human Biology, Kyoto University, Kyoto, Japan
  13. 13Department of Medical Genetics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  14. 14Department of Neurology, JA Nagano Koseiren, Kakeyu-Misayama Rehabilitation Center Kakeyu Hospital, Ueda, Japan
  15. 15Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Japan
  1. Correspondence to Professor Naomichi Matsumoto, Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan; naomat{at}yokohama-cu.ac.jp; Professor Ichiro Yabe, Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan; yabe{at}med.hokudai.ac.jp

Abstract

Background Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity.

Methods We screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion.

Results In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5′-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%–1.26%).

Conclusions FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.

  • GENETICS
  • CEREBELLAR ATAXIA

Data availability statement

The anonymised data obtained in this study are available from the corresponding author on reasonable request.

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Data availability statement

The anonymised data obtained in this study are available from the corresponding author on reasonable request.

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Footnotes

  • X @VANVANVAN1965

  • SM, HD, HY and EK contributed equally.

  • Contributors SM, HD, HY, FT, IY and NM contributed to the conception and design of the study; EK, NK, TMatsubara, YM, KK, YS, TT, SS, MM, MO, TW, MK, KJ, RM, YO, TMiyama, MS, AF, YU, NT, KM, KH, HH, TMizuguchi, HM, YI, TS, KY, HA, FT, IY and NM contributed to the acquisition and analysis of data; SM and NM contributed to drafting the text. All authors approved the manuscript. NM is responsible for the overall content as guarantor.

  • Funding This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP23ek0109674, JP23ek0109549, JP23ek0109617 (NM), JP23ek0109648 (FT, NM and HD) and JP23bm1423020 (HD and FT); JSPS KAKENHI under grant numbers JP23H02829 (SM) and JP21K07869 (EK); the Research Committee on the Medical Basis of Motor Ataxias, Health and Labor Sciences Research Grants of the Ministry of Health, Labor and Welfare, Japan under grant number 23FC1010 (IY) and the Takeda Science Foundation with no grant numbers (TMizuguchi and NM).

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.