TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

被引：293

作者：

Wu, N. ^{[1
]}

Ming, X. ^{[6
,7
]}

Xiao, J. ^{[6
,7
,8
]}

Wu, Z. ^{[1
]}

Chen, X. ^{[5
]}

Shinawi, M. ^{[14
]}

Shen, Y. ^{[9
,16
,17
]}

Yu, G. ^{[6
,7
]}

Liu, J. ^{[1
]}

Xie, H. ^{[5
]}

Gucev, Z. S. ^{[18
]}

Liu, S. ^{[1
]}

Yang, N. ^{[6
,7
]}

Al-Kateb, H. ^{[15
]}

Chen, J. ^{[1
]}

Zhang, Jian ^{[6
,7
]}

Hauser, N. ^{[19
]}

Zhang, T. ^{[5
,10
]}

Tasic, V. ^{[18
]}

Liu, P. ^{[20
]}

Su, X. ^{[1
]}

Pan, X. ^{[6
,7
]}

Liu, C. ^{[11
]}

Wang, L.

Shen, Joseph ^{[19
]}

Shen, Jianxiong ^{[1
]}

Chen, Y. ^{[6
,7
]}

Zhang, T. ^{[5
,10
]}

Zhang, Jianguo ^{[1
]}

Choy, K. W. ^{[12
]}

Wang, Jun

Wang, Q. ^{[6
,7
]}

Li, S. ^{[1
]}

Zhou, W. ^{[6
,7
]}

Guo, J. ^{[5
]}

Wang, Y. ^{[1
]}

Zhang, C. ^{[6
,7
]}

Zhao, H. ^{[1
]}

An, Y. ^{[6
,7
]}

Zhao, Y. ^{[1
]}

Wang, Jiucun ^{[6
,7
,13
]}

Liu, Z. ^{[1
]}

Zuo, Y. ^{[1
]}

Tian, Y. ^{[1
]}

Weng, X. ^{[1
]}

Sutton, V. R. ^{[20
,22
]}

Wang, H. ^{[6
,7
,8
]}

Ming, Y. ^{[2
]}

Kulkarni, S. ^{[15
]}

Zhong, T. P. ^{[6
,7
,8
]}

机构：

[1] Peking Union Med Coll Hosp, Dept Orthoped Surg, Beijing, Peoples R China

[2] Canc Hosp, PET CT Ctr, Beijing, Peoples R China

[3] Peking Union Med Coll, Inst Basic Med Sci, McKusick Zhang Ctr Genet Med, Beijing 100021, Peoples R China

[4] Peking Union Med Coll, Inst Basic Med Sci, State Key Lab Med Mol Biol, Beijing 100021, Peoples R China

[5] Capital Inst Pediat, Affiliated Childrens Hosp, Beijing Municipal Key Lab Child Dev & Nutri, Beijing, Peoples R China

[6] Fudan Univ, State Key Lab Genet Engn, Sch Life Sci, Shanghai 200438, Peoples R China

[7] Fudan Univ, Minist Educ, Sch Life Sci, Key Lab Contemporary Anthropol, Shanghai 200438, Peoples R China

[8] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, Shanghai 200438, Peoples R China

[9] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Sch Med, Shanghai 200030, Peoples R China

[10] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Dept Gastroenterol Hepatol & Nutr, Shanghai 200030, Peoples R China

[11] Nanjing Med Univ, Sch Basic Med Sci, Dept Biotechnol, Nanjing, Jiangsu, Peoples R China

[12] Chinese Univ Hong Kong, Dept Obstet & Gynaecol, Hong Kong, Hong Kong, Peoples R China

[13] Fudan Taizhou Inst Hlth Sci, Taizhou, Peoples R China

[14] Washington Univ, Sch Med, Div Genet & Genom Med, Dept Pediat, St Louis, MO 63130 USA

[15] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA

[16] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[17] Boston Childrens Hosp, Dept Lab Med, Boston, MA USA

[18] Univ Childrens Hosp, Med Fac Skopje, Dept Endocrinol & Genet, Skopje, North Macedonia

[19] Childrens Hosp Cent Calif, Dept Med Genet & Metab, Madera, CA USA

[20] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[21] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[22] Texas Childrens Hosp, Houston, TX 77030 USA

[23] Univ Wisconsin, Dept Pediat, Madison, WI 53706 USA

[24] Univ New S Wales, Victor Chang Cardiac Res Inst, Dev & Stem Cell Biol Div, Sydney, NSW, Australia

[25] Univ New S Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW, Australia

[26] Univ New S Wales, Fac Sci, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2015年 / 372卷 / 04期

基金：

北京市自然科学基金; 中国国家自然科学基金; 英国医学研究理事会;

关键词：

DOMINANT SPONDYLOCOSTAL DYSOSTOSIS; GENE-ENVIRONMENT INTERACTION; VERTEBRAL ANOMALIES; MOUSE EMBRYOS; MUTATION; 16P11.2; ETIOLOGY; MICRODELETION; SEGMENTATION; DISORDERS;

D O I：

10.1056/NEJMoa1406829

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. METHODS We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chainreaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. RESULTS We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8x10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1x10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. CONCLUSIONS Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed.

引用

页码：341 / 350

页数：10

共 44 条

[1] Scoliosis and Vertebral Anomalies: Additional Abnormal Phenotypes Associated with Chromosome 16p11.2 Rearrangement [J].

Al-Kateb, Hussam ;

Khanna, Geetika ;

Filges, Isabel ;

Hauser, Natalie ;

Grange, Dorothy K. ;

Shen, Joseph ;

Smyser, Christopher D. ;

Kulkarni, Shashikant ;

Shinawi, Marwan .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2014, 164 (05) :1118-1126

[2] Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome [J].

Albers, Cornelis A. ;

Paul, Dirk S. ;

Schulze, Harald ;

Freson, Kathleen ;

Stephens, Jonathan C. ;

Smethurst, Peter A. ;

Jolley, Jennifer D. ;

Cvejic, Ana ;

Kostadima, Myrto ;

Bertone, Paul ;

Breuning, Martijn H. ;

Debili, Najet ;

Deloukas, Panos ;

Favier, Remi ;

Fiedler, Janine ;

Hobbs, Catherine M. ;

Huang, Ni ;

Hurles, Matthew E. ;

Kiddle, Graham ;

Krapels, Ingrid ;

Nurden, Paquita ;

Ruivenkamp, Claudia A. L. ;

Sambrook, Jennifer G. ;

Smith, Kenneth ;

Stemple, Derek L. ;

Strauss, Gabriele ;

Thys, Chantal ;

van Geet, Chris ;

Newbury-Ecob, Ruth ;

Ouwehand, Willem H. ;

Ghevaert, Cedric .

NATURE GENETICS, 2012, 44 (04) :435-U248

[3] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[4] Passaging and colony expansion of human pluripotent stem cells by enzyme-free dissociation in chemically defined culture conditions [J].

Beers, Jeanette ;

Gulbranson, Daniel R. ;

George, Nicole ;

Siniscalchi, Lauren I. ;

Jones, Jeffrey ;

Thomson, James A. ;

Chen, Guokai .

NATURE PROTOCOLS, 2012, 7 (11) :2029-2040

[5] Detection of Clinically Relevant Exonic Copy-Number Changes by Array CGH [J].

Boone, Philip M. ;

Bacino, Carlos A. ;

Shaw, Chad A. ;

Eng, Patricia A. ;

Hixson, Patricia M. ;

Pursley, Amber N. ;

Kang, Sung-Hae L. ;

Yang, Yaping ;

Wiszniewska, Joanna ;

Nowakowska, Beata A. ;

del Gaudio, Daniela ;

Xia, Zhilian ;

Simpson-Patel, Gayle ;

Immken, LaDonna L. ;

Gibson, James B. ;

Tsai, Anne C. -H. ;

Bowers, Jennifer A. ;

Reimschisel, Tyler E. ;

Schaaf, Christian P. ;

Potocki, Lorraine ;

Scaglia, Fernando ;

Gambin, Tomasz ;

Sykulski, Maciej ;

Bartnik, Magdalena ;

Derwinska, Katarzyna ;

Wisniowiecka-Kowalnik, Barbara ;

Lalani, Seema R. ;

Probst, Frank J. ;

Bi, Weimin ;

Beaudet, Arthur L. ;

Patel, Ankita ;

Lupski, James R. ;

Cheung, Sau Wai ;

Stankiewicz, Pawel .

HUMAN MUTATION, 2010, 31 (12) :1326-1342

[6] Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6 [J].

Chapman, DL ;

Papaioannou, VE .

NATURE, 1998, 391 (6668) :695-697

[7] Prediction of mRNA polyadenylation sites by support vector machine [J].

Cheng, Yiming ;

Miura, Robert M. ;

Tian, Bin .

BIOINFORMATICS, 2006, 22 (19) :2320-2325

[8] Uncovering the roles of rare variants in common disease through whole-genome sequencing [J].

Cirulli, Elizabeth T. ;

Goldstein, David B. .

NATURE REVIEWS GENETICS, 2010, 11 (06) :415-425

[9] An integrated encyclopedia of DNA elements in the human genome [J].

Dunham, Ian ;

Kundaje, Anshul ;

Aldred, Shelley F. ;

Collins, Patrick J. ;

Davis, CarrieA. ;

Doyle, Francis ;

Epstein, Charles B. ;

Frietze, Seth ;

Harrow, Jennifer ;

Kaul, Rajinder ;

Khatun, Jainab ;

Lajoie, Bryan R. ;

Landt, Stephen G. ;

Lee, Bum-Kyu ;

Pauli, Florencia ;

Rosenbloom, Kate R. ;

Sabo, Peter ;

Safi, Alexias ;

Sanyal, Amartya ;

Shoresh, Noam ;

Simon, Jeremy M. ;

Song, Lingyun ;

Trinklein, Nathan D. ;

Altshuler, Robert C. ;

Birney, Ewan ;

Brown, James B. ;

Cheng, Chao ;

Djebali, Sarah ;

Dong, Xianjun ;

Dunham, Ian ;

Ernst, Jason ;

Furey, Terrence S. ;

Gerstein, Mark ;

Giardine, Belinda ;

Greven, Melissa ;

Hardison, Ross C. ;

Harris, Robert S. ;

Herrero, Javier ;

Hoffman, Michael M. ;

Iyer, Sowmya ;

Kellis, Manolis ;

Khatun, Jainab ;

Kheradpour, Pouya ;

Kundaje, Anshul ;

Lassmann, Timo ;

Li, Qunhua ;

Lin, Xinying ;

Marinov, Georgi K. ;

Merkel, Angelika ;

Mortazavi, Ali .

NATURE, 2012, 489 (7414) :57-74

[10] The Association Analysis of TBX6 Polymorphism With Susceptibility to Congenital Scoliosis in a Chinese Han Population [J].

Fei, Qi ;

Wu, Zhihong ;

Wang, Hai ;

Zhou, Xi ;

Wang, Naiguo ;

Ding, Yaozhong ;

Wang, Yipeng ;

Qiu, Guixing .

SPINE, 2010, 35 (09) :983-988

← 1 2 3 4 5 →