|Title||TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Liu, J, Wu, N, Yang, N, Takeda, K, Chen, W, Li, W, Du, R, Liu, S, Zhou, Y, Zhang, L, Liu, Z, Zuo, Y, Zhao, S, Blank, R, Pehlivan, D, Dong, S, Zhang, J, Shen, J, Si, N, Wang, Y, Liu, G, Li, S, Zhao, Y, Zhao, H, Chen, Y, Zhao, Y, Song, X, Hu, J, Lin, M, Tian, Y, Yuan, B, Yu, K, Niu, Y, Yu, B, Li, X, Chen, J, Yan, Z, Zhu, Q, Meng, X, Chen, X, Su, J, Zhao, X, Wang, X, Ming, Y, Li, X, Raggio, CL, Zhang, B, Weng, X, Zhang, S, Zhang, X, Watanabe, K, Matsumoto, M, Jin, L, Shen, Y, Sobreira, NL, Posey, JE, Giampietro, PF, Valle, D, Liu, P, Wu, Z, Ikegawa, S, Lupski, JR, Zhang, F, Qiu, G|
|Corporate Authors||Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Japan Early Onset Scoliosis Research Group, Baylor-Hopkins Center for Mendelian Genomics|
|Date Published||2019 Jul|
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), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 × 10); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10), while intraspinal anomalies were uncommon (P = 7.0 × 10). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10). A Tbx6 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.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC6659397|
|Grant List||K08 HG008986 / HG / NHGRI NIH HHS / United States |
UM1 HG006542 / HG / NHGRI NIH HHS / United States