@article{25c87bebfe8641c3978b26760a5c7f8a,
title = "TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease",
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.",
keywords = "TBX6 gene, compound inheritance model, congenital scoliosis (CS), gene dosage, genotype–phenotype correlation",
author = "Weisheng Chen and Jiachen Lin and Lianlei Wang and Xiaoxin Li and Sen Zhao and Jiaqi Liu and Akdemir, {Zeynep C.} and Yanxue Zhao and Renqian Du and Yongyu Ye and Xiaofei Song and Yuanqiang Zhang and Zihui Yan and Xinzhuang Yang and Mao Lin and Jianxiong Shen and Shengru Wang and Na Gao and Ying Yang and Ying Liu and Wenli Li and Jia Liu and Na Zhang and Xu Yang and Yuan Xu and Jianguo Zhang and Delgado, {Mauricio R.} and Posey, {Jennifer E.} and Guixing Qiu and Rios, {Jonathan J.} and Pengfei Liu and Wise, {Carol A.} and Feng Zhang and Zhihong Wu and Lupski, {James R.} and Nan Wu",
note = "Funding Information: We would like to thank all the individuals involved in the study for their participation. We thank the nurses from the Department of Orthopedic Surgery of Peking Union Medical College Hospital for assistance with patient enrollment. We thank the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences for providing human HeLa cell lines. This study was funded in part by the National Natural Science Foundation of China (81822030 to N. W., 81772299 and 81930068 to Z. W., 81772301 and 81972132 to G. Q., 81672123 and 81972037 to J. Z.), Beijing Natural Science Foundation (7172175 to N. W., 7191007 to Z. W.), 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine (to N. W.), CAMS Initiative Fund for Medical Sciences (2016-I2M-3-003 to G. Q. and N. W., 2016-I2M-2–006 and 2017-I2M-2-001 to Z. W.), the Central Level Public Interest Program for Scientific Research Institute (2018RC31003 to N. W.), the National Key Research and Development Program of China (No. 2018YFC0910506 to N. W. and Z. W.). Also supported by the US National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS R35 NS105078 to J. R. L.), National Human Genome Research Institute/National Heart, Lung, and Blood Institute (NHGRI/NHLBI UM1 HG006542 to J. R. L.), and the National Human Genome Research Institute (NHGRI K08 HG008986 to J. E. P.). Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",
year = "2020",
month = jan,
day = "1",
doi = "10.1002/humu.23907",
language = "English (US)",
volume = "41",
pages = "182--195",
journal = "Human mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "1",
}