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


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.

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Figure1. The schematic view of six TBX6 gene‐disruptive variants.

Figure 2. Intracellular distribution of mutant TBX6 proteins.

Figure 3. Spinal radiographs of TBX6‐associated congenital scoliosis (TACS) patients.

Figure 4. Gene dosage model of TBX6‐associated congenital scoliosis (TACS)

Department of orthopedic surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS)

Beijing Key Laboratory for Genetic Research of Skeletal Deformity

Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences

Tel: +86-10-69152809

E-mail: dr.wunan@pumch.cn

Address: Department of orthopedic surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, China

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