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

• Published in: Human mutation Vol. 41; no. 1; pp. 182 - 195
• Main Authors: Chen, Weisheng, Lin, Jiachen, Wang, Lianlei, Li, Xiaoxin, Zhao, Sen, Liu, Jiaqi, Akdemir, Zeynep C., Zhao, Yanxue, Du, Renqian, Ye, Yongyu, Song, Xiaofei, Zhang, Yuanqiang, Yan, Zihui, Yang, Xinzhuang, Lin, Mao, Shen, Jianxiong, Wang, Shengru, Gao, Na, Yang, Ying, Liu, Ying, Li, Wenli, Liu, Jia, Zhang, Na, Yang, Xu, Xu, Yuan, Zhang, Jianguo, Delgado, Mauricio R., Posey, Jennifer E., Qiu, Guixing, Rios, Jonathan J., Liu, Pengfei, Wise, Carol A., Zhang, Feng, Wu, Zhihong, Lupski, James R., Wu, Nan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2020
• Subjects: Alleles; Cell Line; compound inheritance model; Congenital defects; congenital scoliosis (CS); Etiology; Female; Gene dosage; Gene Expression; Genes, Reporter; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; genotype–phenotype correlation; Haploinsufficiency; Haplotypes; Heredity; Humans; Inheritance Patterns; Localization; Male; Models, Molecular; Molecular Diagnostic Techniques; Molecular modelling; Mutation, Missense; Phenotype; Phenotypes; Protein Conformation; Radiography; Scoliosis; Sequence Analysis, DNA; Spine - abnormalities; Spine - diagnostic imaging; Structure-Activity Relationship; T-Box Domain Proteins - chemistry; T-Box Domain Proteins - genetics; TBX6 gene; Transcription; Whole Exome Sequencing; gene dosage; compound inheritance model; congenital scoliosis (CS); TBX6 gene; genotype-phenotype correlation
• DOI: 10.1002/humu.23907
• ISSN: 1059-7794; 1098-1004

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. Gene dosage model of TBX6‐associated congenital scoliosis (TACS). The phenotypes in TACS patients vary along with the dosage alterations of TBX6 expression.