TBX6 null variants and a common hypomorphic allele in congenital scoliosis

N Engl J Med. 2015 Jan 22;372(4):341-50. doi: 10.1056/NEJMoa1406829. Epub 2015 Jan 7.

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.).

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Asian Continental Ancestry Group / 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*
  • Scoliosis / diagnostic imaging
  • Scoliosis / genetics*
  • Sequence Deletion
  • Spine / diagnostic imaging
  • T-Box Domain Proteins / genetics*

Substances

  • T-Box Domain Proteins
  • TBX6 protein, human