Dataset Information

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

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.

SUBMITTER: Liu J

PROVIDER: S-EPMC6659397 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Liu Jiaqi J Wu Nan N Yang Nan N Takeda Kazuki K Chen Weisheng W Li Weiyu W Du Renqian R Liu Sen S Zhou Yangzhong Y Zhang Ling L Liu Zhenlei Z Zuo Yuzhi Y Zhao Sen S Blank Robert R Pehlivan Davut D Dong Shuangshuang S Zhang Jianguo J Shen Jianxiong J Si Nuo N Wang Yipeng Y Liu Gang G Li Shugang S Zhao Yanxue Y Zhao Hong H Chen Yixin Y Zhao Yu Y Song Xiaofei X Hu Jianhua J Lin Mao M Tian Ye Y Yuan Bo B Yu Keyi K Niu Yuchen Y Yu Bin B Li Xiaoxin X Chen Jia J Yan Zihui Z Zhu Qiankun Q Meng Xiaolu X Chen Xiaoli X Su Jianzhong J Zhao Xiuli X Wang Xiaoyue X Ming Yue Y Li Xiao X Raggio Cathleen L CL Zhang Baozhong B Weng Xisheng X Zhang Shuyang S Zhang Xue X Watanabe Kota K Matsumoto Morio M Jin Li L Shen Yiping Y Sobreira Nara L NL Posey Jennifer E JE Giampietro Philip F PF Valle David D Liu Pengfei P Wu Zhihong Z Ikegawa Shiro S Lupski James R JR Zhang Feng F Qiu Guixing G

Genetics in medicine : official journal of the American College of Medical Genetics 20190114 7

<h4>Purpose</h4>To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model.<h4>Methods</h4>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 diagnos ...[more]

PMID: 30636772

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Project description:BACKGROUND:We previously reported a novel clinically distinguishable subtype of congenital scoliosis (CS), namely, TBX6-associated congenital scoliosis (TACS). We further developed the TBX6-associated CS risk score (TACScore), a multivariate phenotype-based model to predict TACS according to the patient's clinical manifestations. In this study, we aimed to evaluate whether using the TACScore as a screening method prior to performing whole-exome sequencing (WES) is more cost-effective than using WES as the first-line genetic test for CS. METHODS:We retrospectively collected the molecular data of 416 CS patients in the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study. A decision tree was constructed to estimate the cost and the diagnostic time required for the two alternative strategies (TACScore versus WES). Bootstrapping simulations and sensitivity analyses were performed to examine the distributions and robustness of the estimates. The economic evaluation considered both the health care payer and the personal budget perspectives. RESULTS:From the health care payer perspective, the strategy of using the TACScore as the primary screening method resulted in an average cost of $1074.2 (95%CI: $1044.8 to $1103.5) and an average diagnostic duration of 38.7d (95%CI: 37.8d to 39.6d) to obtain a molecular diagnosis for each patient. In contrast, the corresponding values were $1169.6 (95%CI: $1166.9 to $1172.2) and 41.4d (95%CI: 41.1d to 41.7d) taking WES as the first-line test (P?<?0.001). From the personal budget perspective, patients who were predicted to be positive by the TACScore received a result with an average cost of $715.1 (95%CI: $594.5 to $835.7) and an average diagnostic duration of 30.4d (95%CI: 26.3d to 34.6d). Comparatively, the strategy of WES as the first-line test was estimated to have significantly longer diagnostic time with an average of 44.0d (95%CI: 43.2d to 44.9d), and more expensive with an average of $1193.4 (95%CI: $1185.5 to $1201.3) (P?<?0.001). In 100% of the bootstrapping simulations, the TACScore strategy was significantly less costly and more time-saving than WES. The sensitivity analyses revealed that the TACScore strategy remained cost-effective even when the cost per WES decreased to $8.8. CONCLUSIONS:This retrospective study provides clinicians with economic evidence to integrate the TACScore into clinical practice. The TACScore can be considered a cost-effective tool when it serves as a screening test prior to performing WES.

Dataset Information

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

Publications

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

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