TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model

doi:10.1038/s41436-018-0377-x

科研成果详情

题名	TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model
作者	Liu, Jiaqi 1,2,3; Wu, Nan 1,2,4,5; Yang, Nan 6,7,8; Takeda, Kazuki 9,10; Chen, Weisheng 1,11; Li, Weiyu 6,7; Du, Renqian 5; Liu, Sen 1,2,4; Zhou, Yangzhong 2,12; Zhang, Ling 6,7; Liu, Zhenlei 2,13; Zuo, Yuzhi 1,2,4; Zhao, Sen 1,2; Blank, Robert 14; Pehlivan, Davut 5; Dong, Shuangshuang 6,7; Zhang, Jianguo 1,2,4; Shen, Jianxiong 1,2,4; Si, Nuo 15,16; Wang, Yipeng 1; Liu, Gang 1,2,4; Li, Shugang 1; Zhao, Yanxue 1,2; Zhao, Hong 1; Chen, Yixin 1,2; Zhao, Yu 1; Song, Xiaofei 5; Hu, Jianhua 1; Lin, Mao 1,2,11; Tian, Ye 1; Yuan, Bo 5; Yu, Keyi 1; Niu, Yuchen 2,17; Yu, Bin 1; Li, Xiaoxin 2,17; Chen, Jia 1,2; Yan, Zihui 1,2,11; Zhu, Qiankun 1,2; Meng, Xiaolu 15,16; Chen, Xiaoli 18; Su, Jianzhong19; Zhao, Xiuli 15,16; Wang, Xiaoyue 16; Ming, Yue 20; Li, Xiao 21; Raggio, Cathleen L.22; Zhang, Baozhong 1; Weng, Xisheng 1,2,4; Zhang, Shuyang 2,23; Zhang, Xue 2,15,16; Watanabe, Kota 10; Matsumoto, Morio 10; Jin, Li 6; Shen, Yiping 24,25; Sobreira, Nara L.26; Posey, Jennifer E.5; Giampietro, Philip F.27; Valle, David 26; Liu, Pengfei 5,28; Wu, Zhihong 2,4,17; Ikegawa, Shiro 9; Lupski, James R.5,29,30; Zhang, Feng 6,7,8; Qiu, Guixing 1,2,4
发表日期	2019-07
发表期刊	GENETICS IN MEDICINE 影响因子和分区
语种	英语
原始文献类型	Article
关键词	congenital scoliosis (CS) 16p11.2/TBX6 compound inheritance model genotype-phenotype correlation gene dosage
其他关键词	MOUSE EMBRYOS ; 16P11.2 ; MUTATIONS ; ANOMALIES ; DIAGNOSIS
摘要	Purpose: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. Methods: Patients with congenital scoliosis (CS) from China (N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N= 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). Results: In cohort 1, TACS patients (N= 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 x 10(-8)), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 x 10(-3)); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TAGS patients (P = 3.1 x 10(-7)), while intraspinal anomalies were uncommon (P = 7.0 x 10(-7)). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 x 10(-15)). A Tbx6(-/mh (mild-hypomorphic)) mouse model supported that a gene dosage effect underlies the TACS phenotype. Conclusion: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81822030, 81501852, 81472045, 81772301, 31625015, 31571297, 31771396, 81472046, 81772299, 31521003, 81672123, 7162029]; Beijing Natural Science FoundationBeijing Natural Science Foundation [7162029, 7172175]; Beijing Nova ProgramBeijing Municipal Science & Technology Commission [Z161100004916123]; Beijing Nova Program Interdisciplinary Collaborative Project [xxjc201717]; 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine; Central Level Public Interest Program for Scientific Research Institute [2016ZX310177]; Fundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities [3332016006]; Chinese Academy of Medical Sciences (CAMS) Initiative Fund for Medical Sciences [2016-I2M-3-003, 2016-I2M-2-006, 2017-I2M-2-001]; Distinguished Youth Foundation of Peking Union Medical College Hospital [JQ201506]; PUMCH Science Fund for Junior Faculty [PUMCH-2016-1.1]; National Key Research and Development Program of China [2016YFC0901501]; Japan Agency for Medical Research and Development (AMED)Japan Agency for Medical Research and Development (AMED) [17ek0109280h0001, 17824969]; Japan Orthopedics and Traumatology Research Foundation [358]; US National Institutes of Health, National Institute of Neurological Disorders and StrokeUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [NINDS R01 NS058529, R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; National Human Genome Research InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [NHGRI K08 HG008986]; PUMC Youth Fund; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08HG008986, UM1HG006542] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078, R01NS058529] Funding Source: NIH RePORTER
出版者	NATURE PUBLISHING GROUP
出版地	NEW YORK
ISSN	1098-3600
EISSN	1530-0366
卷号	21 期号:7 页码:1548-1558
DOI	10.1038/s41436-018-0377-x
页数	11
WOS类目	Genetics & Heredity
WOS研究方向	Genetics & Heredity
WOS记录号	WOS:000473518700013
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	30636772
PMC记录号	PMC6659397
SCOPUSEID	2-s2.0-85060096647
自科自定义期刊分类	T3(B)类
通讯作者地址	[Wu, Nan]Department of Orthopedic Surgery,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China
Scopus学科分类	Genetics (clinical)
引用统计	被引频次：35[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/20777
专题	眼视光学院（生物医学工程学院）、附属眼视光医院_生物医学信息系
通讯作者	Wu, Nan
作者单位	1.Department of Orthopedic Surgery,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China; 2.Beijing Key Laboratory for Genetic Research of Skeletal Deformity,Beijing,China; 3.Department of Breast Surgical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China; 4.Medical Research Center of Orthopedics,Chinese Academy of Medical Sciences,Beijing,China; 5.Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,United States; 6.Obstetrics and Gynecology Hospital,State Key Laboratory of Genetic Engineering at School of Life Sciences,Institute of Metabolism and Integrative Biology,Fudan University,Shanghai,China; 7.NHC Key Laboratory of Reproduction Regulation,Shanghai Institute of Planned Parenthood Research,Fudan University,Shanghai,China; 8.Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases,Shanghai,China; 9.Laboratory of Bone and Joint Diseases,Center for Integrative Medical Sciences,RIKEN,Tokyo,Japan; 10.Department of Orthopedic Surgery,Keio University School of Medicine,Tokyo,Japan; 11.Graduate School of Peking Union Medical College,Beijing,China; 12.Department of Internal Medicine,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China; 13.Department of Neurosurgery,Xuanwu Hospital,Capital Medical University,Beijing,China; 14.Department of Medicine,Medical College of Wisconsin,Milwaukee,United States; 15.The McKusick–Zhang Center for Genetic Medicine,Institute of Basic Medical Sciences,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China; 16.The State Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China; 17.Department of Central Laboratory,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China; 18.Department of Medical Genetics,Capital Institute of Pediatrics,Beijing,China; 19.College of Biomedical Engineering,The Eye Hospital,Wenzhou Medical University,Wenzhou,Zhejiang,China; 20.PET-CT Center,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China; 21.Department of Radiology,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China; 22.Department of Orthopedic Surgery,Hospital for Special Surgery,New York,United States; 23.Department of Cardiology,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,China; 24.Division of Genetics and Genomics,Boston Children’s Hospital,Boston,United States; 25.Harvard Medical School,Boston,United States; 26.McKusick-Nathans Institute of Genetic Medicine,Johns Hopkins University School of Medicine,Baltimore,United States; 27.Department of Pediatrics,Drexel University College of Medicine,Philadelphia,United States; 28.Baylor Genetics Laboratory,Houston,United States; 29.Departments of Pediatrics,Baylor College of Medicine,Houston,United States; 30.Texas Children’s Hospital,Houston,United States
推荐引用方式 GB/T 7714	Liu, Jiaqi,Wu, Nan,Yang, Nan,et al. TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model[J]. GENETICS IN MEDICINE,2019,21(7):1548-1558.
APA	Liu, Jiaqi., Wu, Nan., Yang, Nan., Takeda, Kazuki., Chen, Weisheng., ... & Qiu, Guixing. (2019). TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model. GENETICS IN MEDICINE, 21(7), 1548-1558.
MLA	Liu, Jiaqi,et al."TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model".GENETICS IN MEDICINE 21.7(2019):1548-1558.