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Original research
Long-read sequencing identifies an SVA_D retrotransposon insertion deep within the intron of ATP7A as a novel cause of occipital horn syndrome
  1. Naoko Yano1,
  2. Pin Fee Chong2,3,
  3. Kenji K Kojima4,
  4. Tomoichiro Miyoshi5,6,
  5. Ahmad Luqmen-Fatah5,
  6. Yu Kimura7,
  7. Kengo Kora1,
  8. Taisei Kayaki1,
  9. Kanako Maizuru8,
  10. Takahiro Hayashi9,
  11. Atsushi Yokoyama1,
  12. Masahiko Ajiro10,
  13. Masatoshi Hagiwara11,12,
  14. Teruyuki Kondo7,
  15. Ryutaro Kira2,
  16. Junko Takita1,
  17. Takeshi Yoshida1
  1. 1Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
  2. 2Department of Pediatric Neurology, Fukuoka Children’s Hospital, Fukuoka, Japan
  3. 3Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  4. 4Genetic Information Research Institute, Cupertino, CA, USA
  5. 5Laboratory for Retrotransposon Dynamics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  6. 6Department of Gene Mechanisms, Kyoto University Graduate School of Biostudies, Kyoto, Japan
  7. 7Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
  8. 8Department of Pediatrics, Tenri Yorozu Hospital, Tenri, Japan
  9. 9Department of Pediatrics, Kurashiki Central Hospital, Kurashiki, Japan
  10. 10Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo, Japan
  11. 11Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  12. 12Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  1. Correspondence to Dr Takeshi Yoshida, Department of Pediatrics, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, Japan; tayoshi{at}


Background SINE-VNTR-Alu (SVA) retrotransposons move from one genomic location to another in a ‘copy-and-paste’ manner. They continue to move actively and cause monogenic diseases through various mechanisms. Currently, disease-causing SVA retrotransposons are classified into human-specific young SVA_E or SVA_F subfamilies. In this study, we identified an evolutionarily old SVA_D retrotransposon as a novel cause of occipital horn syndrome (OHS). OHS is an X-linked, copper metabolism disorder caused by dysfunction of the copper transporter, ATP7A.

Methods We investigated a 16-year-old boy with OHS whose pathogenic variant could not be detected via routine molecular genetic analyses.

Results A 2.8 kb insertion was detected deep within the intron of the patient’s ATP7A gene. This insertion caused aberrant mRNA splicing activated by a new donor splice site located within it. Long-read circular consensus sequencing enabled us to accurately read the entire insertion sequence, which contained highly repetitive and GC-rich segments. Consequently, the insertion was identified as an SVA_D retrotransposon. Antisense oligonucleotides (AOs) targeting the new splice site restored the expression of normal transcripts and functional ATP7A proteins. AO treatment alleviated excessive accumulation of copper in patient fibroblasts in a dose-dependent manner. Pedigree analysis revealed that the retrotransposon had moved into the OHS-causing position two generations ago.

Conclusion This is the first report of a human monogenic disease caused by the SVA_D retrotransposon. The fact that the evolutionarily old SVA_D is still actively transposed, leading to increased copy numbers may make a notable impact on rare genetic disease research.

  • Neurology
  • Genetic Diseases, X-Linked
  • Pediatrics
  • Sequence Analysis

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • Contributors NY and TY designed the study and wrote the manuscript draft. NY, PFC, KKK, AL-F, TM, YK, KK, KM and TH collected and analysed the data. NY, TM, KKK, AY, MA, MH, TK, RK, JT and TY interpreted the results. All authors have reviewed and revised the manuscript. All authors have approved the final version of the manuscript for publication. TY is responsible for the overall content as guarantor.

  • Funding This study was supported by a JSPS Grant-in-Aid for Research Activity Start up awarded to NY. (grant number: 23K19588).

  • 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.