TBX6 null variants and a common hypomorphic allele in congenital scoliosis

Nan Wu, Xuan Ming, Jianqiu Xiao, Zhihong Wu, Xiaoli Chen, Marwan Shinawi, Yiping Shen, Guangju Yu, Jiaqi Liu, Hua Xie, Zoran S. Gucev, Sen Liu, Nan Yang, Hussam Al-Kateb, Jun Chen, Jian Zhang, Natalie Hauser, Ting Zhang, Velibor Tasic, Pengfei LiuXinlin Su, Xuedong Pan, Chunyu Liu, Liwen Wang, Joseph Shen, Jianxiong Shen, Yulin Chen, Ting Zhang, Jianguo Zhang, Kwong Wai Choy, Jun Wang, Qiqi Wang, Shugang Li, Weichen Zhou, Jin Guo, Yipeng Wang, Cheng Zhang, Hong Zhao, Yu An, Yu Zhao, Jiucun Wang, Zhenlei Liu, Yuzhi Zuo, Ye Tian, Xisheng Weng, V. Reid Sutton, Hongyan Wang, Yue Ming, Shashikant Kulkarni, Tao P. Zhong, Philip F. Giampietro, Sally L. Dunwoodie, Sau Wai Cheung, Xue Zhang, Li Jin, James R. Lupski, Guixing Qiu, Feng Zhang

Research output: Contribution to journalArticlepeer-review

184 Scopus citations


Background: Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. Methods: We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. Results: We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10-6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6 ) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10-6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. Conclusions: Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed.

Original languageEnglish
Pages (from-to)341-350
Number of pages10
JournalNew England Journal of Medicine
Issue number4
StatePublished - Jan 22 2015


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