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

TitleTBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.
Publication TypeJournal Article
Year of Publication2019
AuthorsLiu, 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 AuthorsDeciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Japan Early Onset Scoliosis Research Group, Baylor-Hopkins Center for Mendelian Genomics
JournalGenet Med
Volume21
Issue7
Pagination1548-1558
Date Published2019 Jul
ISSN1530-0366
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), 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.

DOI10.1038/s41436-018-0377-x
Alternate JournalGenet. Med.
PubMed ID30636772
PubMed Central IDPMC6659397
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States