Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis

Nao Otomo, Kazuki Takeda, Shunsuke Kawai, Ikuyo Kou, Long Guo, Mitsujiro Osawa, Cantas Alev, Noriaki Kawakami, Noriko Miyake, Naomichi Matsumoto, Yukuto Yasuhiko, Toshiaki Kotani, Teppei Suzuki, Koki Uno, Hideki Sudo, Satoshi Inami, Hiroshi Taneichi, Hideki Shigematsu, Kei Watanabe, Ikuho YonezawaRyo Sugawara, Yuki Taniguchi, Shohei Minami, Kazuo Kaneko, Masaya Nakamura, Morio Matsumoto, Junya Toguchida, Kota Watanabe, Shiro Ikegawa

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)622-628
Number of pages7
JournalJournal of medical genetics
Issue number9
Publication statusPublished - 2019 Sept 1


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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