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

Weisheng Chen, Jiachen Lin, Lianlei Wang, Xiaoxin Li, Sen Zhao, Jiaqi Liu, Zeynep C. Akdemir, Yanxue Zhao, Renqian Du, Yongyu Ye, Xiaofei Song, Yuanqiang Zhang, Zihui Yan, Xinzhuang Yang, Mao Lin, Jianxiong Shen, Shengru Wang, Na Gao, Ying Yang, Ying LiuWenli Li, Jia Liu, Na Zhang, Xu Yang, Yuan Xu, Jianguo Zhang, Mauricio R. Delgado, Jennifer E. Posey, Guixing Qiu, Jonathan J. Rios, Pengfei Liu, Carol A. Wise, Feng Zhang, Zhihong Wu, James R. Lupski, Nan Wu

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)182-195
Number of pages14
JournalHuman mutation
Issue number1
StatePublished - Jan 1 2020


  • TBX6 gene
  • compound inheritance model
  • congenital scoliosis (CS)
  • gene dosage
  • genotype–phenotype correlation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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