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

TitleTBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsChen, W, Lin, J, Wang, L, Li, X, Zhao, S, Liu, J, Akdemir, ZC, Zhao, Y, Du, R, Ye, Y, Song, X, Zhang, Y, Yan, Z, Yang, X, Lin, M, Shen, J, Wang, S, Gao, N, Yang, Y, Liu, Y, Li, W, Liu, J, Zhang, N, Yang, X, Xu, Y, Zhang, J, Delgado, MR, Posey, JE, Qiu, G, Rios, JJ, Liu, P, Wise, CA, Zhang, F, Wu, Z, Lupski, JR, Wu, N
JournalHum Mutat
Date Published2020 Jan
KeywordsAlleles, 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, Structure-Activity Relationship, T-Box Domain Proteins

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.

Alternate JournalHum Mutat
PubMed ID31471994
PubMed Central IDPMC7061259
Grant ListP01 HD084387 / HD / NICHD NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
NHGRI/NHLBI UM1 HG00654 / / US National Human Genome Research Institute / International

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