先天性脊柱侧凸中TBX6无效变异体和一种常见亚效等位基因

TBX6 null variants and a common hypomorphic allele in congenital scoliosis
2015-09-15 12:02发表评论
作者:Wu N., Ming X., Xiao J., Wu Z., Chen X., Shinawi M., Shen Y., Yu G., Liu J., Xie H., Gucev Z.S., Liu S., Yang N., Al-Kateb H., Chen J., Zhang J., Hauser N., Zhang T., Tasic V., Liu P., Su X., Pan X., Liu C., Wang L., Shen J., Shen J., Chen Y., Zhang T., Zhang J., Choy K.W., Wang J., Wang Q., Li S., Zhou W., Guo J., Wang Y., Zhang C., Zhao H., An Y., Zhao Y., Wang J., Liu Z., Zuo Y., Tian Y., Weng X., Sutton V.R., Wang H., Ming Y., Kulkarni S., Zhong T.P., Giampietro P.F., Dunwoodie S.L., Cheung S.W., Zhang X., Jin L., Lupski J.R., Qiu G., Zhang F.
机构: 北京协和医院整形外科
期刊: NEW ENGL J MED 2015年1月4期372卷

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. Copyright © 2015 Massachusetts Medical Society.

通讯机构:Department of Orthopedic Surgery, Peking Union Medical College Hospital, Capital Institute of Pediatrics, No. 1 Shuaifuyuan, Beijing, China
学科代码:内科学   关键词:先天性脊柱侧凸 TBX6无效变异体 ,中国作者重要发表 爱思唯尔医学网, Elseviermed
来源: Scopus
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