학술논문
TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model
Document Type
Original Paper
Author
Liu, Jiaqi; Wu, Nan; Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study; Yang, Nan; Takeda, Kazuki; Chen, Weisheng; Li, Weiyu; Du, Renqian; Liu, Sen; Zhou, Yangzhong; Zhang, Ling; Liu, Zhenlei; Zuo, Yuzhi; Zhao, Sen; Blank, Robert; Pehlivan, Davut; Dong, Shuangshuang; Zhang, Jianguo; Shen, Jianxiong; Si, Nuo; Wang, Yipeng; Liu, Gang; Li, Shugang; Zhao, Yanxue; Zhao, Hong; Chen, Yixin; Zhao, Yu; Song, Xiaofei; Hu, Jianhua; Lin, Mao; Tian, Ye; Yuan, Bo; Yu, Keyi; Niu, Yuchen; Yu, Bin; Li, Xiaoxin; Chen, Jia; Yan, Zihui; Zhu, Qiankun; Meng, Xiaolu; Chen, Xiaoli; Su, Jianzhong; Zhao, Xiuli; Wang, Xiaoyue; Ming, Yue; Li, Xiao; Raggio, Cathleen L.; Zhang, Baozhong; Weng, Xisheng; Zhang, Shuyang; Zhang, Xue; Watanabe, Kota; Matsumoto, Morio; Japan Early Onset Scoliosis Research Group; Jin, Li; Shen, Yiping; Sobreira, Nara L.; Posey, Jennifer E.; Giampietro, Philip F.; Valle, David; Baylor-Hopkins Center for Mendelian Genomics; Liu, Pengfei; Wu, Zhihong; Ikegawa, Shiro; Lupski, James R.; Zhang, Feng; Qiu, Guixing
Source
Genetics in Medicine: Official journal of the American College of Medical Genetics and Genomics. 21(7):1548-1558
Subject
Language
English
ISSN
1098-3600
1530-0366
1530-0366
Abstract
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 × 10‒8 ), and exhibited vertebral malformations involving the lower part of the spine (T8–S5, P = 4.4 × 10‒3 ); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10‒7 ), while intraspinal anomalies were uncommon (P = 7.0 × 10‒7 ). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 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.