TY - JOUR
T1 - TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis
T2 - further evidence supporting the compound inheritance and TBX6 gene dosage model
AU - Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study
AU - Japan Early Onset Scoliosis Research Group
AU - Baylor-Hopkins Center for Mendelian Genomics
AU - Liu, Jiaqi
AU - Wu, Nan
AU - Yang, Nan
AU - Takeda, Kazuki
AU - Chen, Weisheng
AU - Li, Weiyu
AU - Du, Renqian
AU - Liu, Sen
AU - Zhou, Yangzhong
AU - Zhang, Ling
AU - Liu, Zhenlei
AU - Zuo, Yuzhi
AU - Zhao, Sen
AU - Blank, Robert
AU - Pehlivan, Davut
AU - Dong, Shuangshuang
AU - Zhang, Jianguo
AU - Shen, Jianxiong
AU - Si, Nuo
AU - Wang, Yipeng
AU - Liu, Gang
AU - Li, Shugang
AU - Zhao, Yanxue
AU - Zhao, Hong
AU - Chen, Yixin
AU - Zhao, Yu
AU - Song, Xiaofei
AU - Hu, Jianhua
AU - Lin, Mao
AU - Tian, Ye
AU - Yuan, Bo
AU - Yu, Keyi
AU - Niu, Yuchen
AU - Yu, Bin
AU - Li, Xiaoxin
AU - Chen, Jia
AU - Yan, Zihui
AU - Zhu, Qiankun
AU - Meng, Xiaolu
AU - Chen, Xiaoli
AU - Su, Jianzhong
AU - Zhao, Xiuli
AU - Wang, Xiaoyue
AU - Ming, Yue
AU - Li, Xiao
AU - Raggio, Cathleen L.
AU - Zhang, Baozhong
AU - Weng, Xisheng
AU - Sobreira, Nara L.
AU - Valle, David
N1 - Publisher Copyright:
© 2019, American College of Medical Genetics and Genomics.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
KW - 16p11.2/TBX6
KW - compound inheritance model
KW - congenital scoliosis (CS)
KW - gene dosage
KW - genotype-phenotype correlation
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U2 - 10.1038/s41436-018-0377-x
DO - 10.1038/s41436-018-0377-x
M3 - Article
C2 - 30636772
AN - SCOPUS:85060096647
SN - 1098-3600
VL - 21
SP - 1548
EP - 1558
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -