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 Publication2019
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 Published2019 Aug 31
ISSN1098-1004
Abstract

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.

DOI10.1002/humu.23907
Alternate JournalHum. Mutat.
PubMed ID31471994
Grant List81672123 / / National Natural Science Foundation of China /
81772299 / / National Natural Science Foundation of China /
81772301 / / National Natural Science Foundation of China /
81822030 / / National Natural Science Foundation of China /
81930068 / / National Natural Science Foundation of China /
81972132 / / National Natural Science Foundation of China /
2016 / / Beijing Natural Science Foundation /
7172175 7191007 / / Beijing Natural Science Foundation /
/ / Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine /
NHGRI/NHLBI UM1 HG00654 / / US National Human Genome Research Institute /
NHGRI K08 HG008986 / / US National Human Genome Research Institute /
2018YFC0910506 / / National Key Research and Development Program of China /
2018RC31003 / / Central Level Public Interest Program for Scientific Research Institute /
NINDS R35 NS105078 / / US National Institute of Neurological Disorders and Stroke /
2016-I2M-3-003 2016-I2M-2-006 2017-I2M-2-001. / / CAMS Initiative Fund for Medical Sciences /