TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease

Hum Mutat. 2020 Jan;41(1):182-195. doi: 10.1002/humu.23907. Epub 2019 Sep 26.


Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

Keywords: TBX6 gene; compound inheritance model; congenital scoliosis (CS); gene dosage; genotype-phenotype correlation.

Publication types

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

MeSH terms

  • Alleles
  • Cell Line
  • Exome Sequencing
  • Female
  • Gene Expression
  • Genes, Reporter
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genotype
  • Haplotypes
  • Humans
  • Inheritance Patterns*
  • Male
  • Models, Molecular
  • Molecular Diagnostic Techniques
  • Mutation, Missense*
  • Phenotype
  • Protein Conformation
  • Radiography
  • Sequence Analysis, DNA
  • Spine / abnormalities
  • Spine / diagnostic imaging
  • Structure-Activity Relationship
  • T-Box Domain Proteins / chemistry
  • T-Box Domain Proteins / genetics*


  • T-Box Domain Proteins
  • TBX6 protein, human