• N Wu, X Ming, J Xiao, Z Wu, X Chen, M Shinawi, Y Shen, G Yu, J Liu, H Xie, Z S Gucev, S Liu, N Yang, H Al-Kateb, J Chen, J Zhang, N Hauser, T Zhang, V Tasic, P Liu, X Su, X Pan, C Liu, L Wang, J Shen, Y Chen, K W Choy, J Wang, Q Wang, S Li, W Zhou, J Guo, Y Wang, C Zhang, Hong Zhao, Yu An, Yu Zhao, Z Liu, Y Zuo, Y Tian, X Weng, V R Sutton, H Wang, Y Ming, S Kulkarni, T P Zhong, P F Giampietro, S L Dunwoodie, S W Cheung, X Zhang, L Jin, J R Lupski, G Qiu, and F Zhang.
• The authors' affiliations are listed in the Appendix.
• N. Engl. J. Med.. 2015 Jan 22;372(4):341-50.

BackgroundCongenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.MethodsWe 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.ResultsWe 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.ConclusionsCompound 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. (Funded by the National Basic Research Program of China and others.).

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