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: 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, J Shen, Y Chen, T Zhang, J Zhang, K W Choy, J Wang, Q Wang, S Li, W Zhou, J Guo, Y Wang, C Zhang, Hong Zhao, Yu An, Yu Zhao, J Wang, 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, F Zhang
• Journal: The New England journal of medicine (N Engl J Med) Vol. 372 Issue 4 Pg. 341-50 (Jan 22 2015) ISSN: 1533-4406 [Electronic] United States
• PMID: 25564734 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• T-Box Domain Proteins
• TBX6 protein, human

Topics

• Adolescent
• Asian People (genetics)
• Child
• Child, Preschool
• Chromosomes, Human, Pair 16
• DNA Copy Number Variations
• Female
• Genetic Predisposition to Disease
• Genotype
• Humans
• Male
• Mutation
• Pedigree
• Phenotype
• Radiography
• Scoliosis (congenital, diagnostic imaging, genetics)
• Sequence Deletion
• Spine (diagnostic imaging)
• T-Box Domain Proteins (genetics)