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Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis
  1. Nao Otomo1,2,
  2. Kazuki Takeda1,2,
  3. Shunsuke Kawai3,4,5,
  4. Ikuyo Kou1,
  5. Long Guo1,
  6. Mitsujiro Osawa6,
  7. Cantas Alev3,
  8. Noriaki Kawakami7,
  9. Noriko Miyake8,
  10. Naomichi Matsumoto8,
  11. Yukuto Yasuhiko9,
  12. Toshiaki Kotani10,
  13. Teppei Suzuki11,
  14. Koki Uno11,
  15. Hideki Sudo12,
  16. Satoshi Inami13,
  17. Hiroshi Taneichi13,
  18. Hideki Shigematsu14,
  19. Kei Watanabe15,
  20. Ikuho Yonezawa16,
  21. Ryo Sugawara17,
  22. Yuki Taniguchi18,
  23. Shohei Minami10,
  24. Kazuo Kaneko16,
  25. Masaya Nakamura2,
  26. Morio Matsumoto2,
  27. Junya Toguchida3,4,5,
  28. Kota Watanabe2,
  29. Shiro Ikegawa1
  1. 1 Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
  2. 2 Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
  3. 3 Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
  4. 4 Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
  5. 5 Department of Orthopedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  6. 6 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
  7. 7 Department of Orthopaedic Surgery, Meijo Hospital, Nagoya, Japan
  8. 8 Department of Human Genetics, Yokohama City University Graduated School of Medicine, Yokohama, Japan
  9. 9 Division of Cellular and Molecular Toxicology, National Institute of Health Sciences, Tokyo, Japan
  10. 10 Department of Orthopedic Surgery, Seirei Sakura Citizen Hospital, Sakura, Japan
  11. 11 Department of Orthopedic Surgery, National Hospital Organization, Kobe Medical Center, Kobe, Japan
  12. 12 Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  13. 13 Department of Orthopedic Surgery, Dokkyo Medical University School of Medicine, Mibu, Japan
  14. 14 Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan
  15. 15 Department of Orthopedic Surgery, Niigata University Hospital, Niigata, Japan
  16. 16 Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan
  17. 17 Department of Orthopedic Surgery, Jichi Medical University, Shimotsuke, Japan
  18. 18 Department of Orthopedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
  1. Correspondence to Shiro Ikegawa, Bone and joint diseases, RIKEN center for Integrative Medical Science, Tokyo 108-8639, Japan; sikegawa{at}; Kota Watanabe, Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan; watakota{at}


Background Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity.

Methods We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments.

Results We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype.

Conclusions Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

  • congenital scoliosis
  • spondylocostal dysostosis
  • TBX6
  • mislocalisation
  • bi-allelic mutation

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  • Contributors All authors contributed to the feedback of the manuscript and played an important role in implementing the study. NO coordinated the study. NO, KT, MN, JT, MM, KoW and SI designed the study. NO, KT, NK, TK, TS, KU, HSu, SI, HT, HSh, KeW, IY, RS, YT, SM, KK, KoW provided patient care and collected samples and data. IK, LG, NoM and NaM performed genetic analysis. NO, KT, SK, MO, AC and YY performed functional analysis. NO, JT, KoW and SI interpreted the results and wrote the manuscript. All authors critically reviewed the report. No writing assistance was provided. NO and SI had full access to all of the data in the study and take responsibility for the integrity of the data. All authors revised the manuscript critically and approved the final version for publication.

  • Funding This work was supported by research grants from Japan Orthopedics and Traumatology Foundation (for NO and KT), Japan Agency For Medical Research and Development (AMED) (contract Nos. 17ek0109212h0001 for SI and 17ek0109280h0001 for SI), the Japan Society for the Promotion of Science (WAKATE B, No. 17K16710 for LG), the Cooperative Research Program (Joint Usage/Research Center program) of Institute for Frontier Life and Medical Sciences, Kyoto University (for SI, LG and JT) and the Acceleration Program for Intractable Disease Research Utilizing Disease Specific iPS Cells (AMED) to JT.

  • Competing interests None declared.

  • Patient consent for publication Informed consent was obtained from the patients or their parents.

  • Ethics approval The Medical Ethics Committee of the Keio University Hospital, Tokyo, approved the study protocol (20080129).

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