title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
abstract: 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. (Funded by the National Basic Research Program of China and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: N
authors.initials: N
authors.lastname: Wu
authors.forename: X
authors.initials: X
authors.lastname: Ming
authors.forename: J
authors.initials: J
authors.lastname: Xiao
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Shinawi
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.forename: G
authors.initials: G
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Xie
authors.forename: Z S
authors.initials: ZS
authors.lastname: Gucev
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: N
authors.initials: N
authors.lastname: Yang
authors.forename: H
authors.initials: H
authors.lastname: Al-Kateb
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: N
authors.initials: N
authors.lastname: Hauser
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.forename: V
authors.initials: V
authors.lastname: Tasic
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.forename: X
authors.initials: X
authors.lastname: Pan
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: K W
authors.initials: KW
authors.lastname: Choy
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Yu
authors.initials: Y
authors.lastname: An
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Zuo
authors.forename: Y
authors.initials: Y
authors.lastname: Tian
authors.forename: X
authors.initials: X
authors.lastname: Weng
authors.forename: V R
authors.initials: VR
authors.lastname: Sutton
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Ming
authors.forename: S
authors.initials: S
authors.lastname: Kulkarni
authors.forename: T P
authors.initials: TP
authors.lastname: Zhong
authors.forename: P F
authors.initials: PF
authors.lastname: Giampietro
authors.forename: S L
authors.initials: SL
authors.lastname: Dunwoodie
authors.forename: S W
authors.initials: SW
authors.lastname: Cheung
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
authors.forename: G
authors.initials: G
authors.lastname: Qiu
authors.forename: F
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002885:Chromosomes, Human, Pair 16; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D012600:Scoliosis / Q000151:congenital* / Q000000981:diagnostic imaging / Q000235:genetics*; D017384:Sequence Deletion; D013131:Spine / Q000000981:diagnostic imaging; D020825:T-Box Domain Proteins / Q000235:genetics*
chemical_list: D020825:T-Box Domain Proteins; C491182:TBX6 protein, human