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To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. 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). 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. 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.

Citation

Jiaqi Liu, Nan Wu, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Nan Yang, Kazuki Takeda, Weisheng Chen, Weiyu Li, Renqian Du, Sen Liu, Yangzhong Zhou, Ling Zhang, Zhenlei Liu, Yuzhi Zuo, Sen Zhao, Robert Blank, Davut Pehlivan, Shuangshuang Dong, Jianguo Zhang, Jianxiong Shen, Nuo Si, Yipeng Wang, Gang Liu, Shugang Li, Yanxue Zhao, Hong Zhao, Yixin Chen, Yu Zhao, Xiaofei Song, Jianhua Hu, Mao Lin, Ye Tian, Bo Yuan, Keyi Yu, Yuchen Niu, Bin Yu, Xiaoxin Li, Jia Chen, Zihui Yan, Qiankun Zhu, Xiaolu Meng, Xiaoli Chen, Jianzhong Su, Xiuli Zhao, Xiaoyue Wang, Yue Ming, Xiao Li, Cathleen L Raggio, Baozhong Zhang, Xisheng Weng, Shuyang Zhang, Xue Zhang, Kota Watanabe, Morio Matsumoto, Japan Early Onset Scoliosis Research Group, Li Jin, Yiping Shen, Nara L Sobreira, Jennifer E Posey, Philip F Giampietro, David Valle, Baylor-Hopkins Center for Mendelian Genomics, Pengfei Liu, Zhihong Wu, Shiro Ikegawa, James R Lupski, Feng Zhang, Guixing Qiu. 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 : official journal of the American College of Medical Genetics. 2019 Jul;21(7):1548-1558

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PMID: 30636772

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