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

Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Japan Early Onset Scoliosis Research Group, Baylor-Hopkins Center for Mendelian Genomics

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
JournalGenetics in Medicine
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Gene Dosage
Scoliosis
Endophenotypes
Spine
Butterflies
Ribs
Area Under Curve
China
Japan
Genotype
Tomography
Phenotype

Keywords

  • 16p11.2/TBX6
  • compound inheritance model
  • congenital scoliosis (CS)
  • gene dosage
  • genotype-phenotype correlation

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Japan Early Onset Scoliosis Research Group, & Baylor-Hopkins Center for Mendelian Genomics (Accepted/In press). 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. https://doi.org/10.1038/s41436-018-0377-x

TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis : further evidence supporting the compound inheritance and TBX6 gene dosage model. / Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study; Japan Early Onset Scoliosis Research Group; Baylor-Hopkins Center for Mendelian Genomics.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Japan Early Onset Scoliosis Research Group & Baylor-Hopkins Center for Mendelian Genomics 2019, '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. https://doi.org/10.1038/s41436-018-0377-x
Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Japan Early Onset Scoliosis Research Group, Baylor-Hopkins Center for Mendelian Genomics. 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. 2019 Jan 1. https://doi.org/10.1038/s41436-018-0377-x
Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study ; Japan Early Onset Scoliosis Research Group ; Baylor-Hopkins Center for Mendelian Genomics. / TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis : further evidence supporting the compound inheritance and TBX6 gene dosage model. In: Genetics in Medicine. 2019.
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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.",
keywords = "16p11.2/TBX6, compound inheritance model, congenital scoliosis (CS), gene dosage, genotype-phenotype correlation",
author = "{Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study} and {Japan Early Onset Scoliosis Research Group} and {Baylor-Hopkins Center for Mendelian Genomics} and Jiaqi Liu and Nan Wu and Nan Yang and Kazuki Takeda and Weisheng Chen and Weiyu Li and Renqian Du and Sen Liu and Yangzhong Zhou and Ling Zhang and Zhenlei Liu and Yuzhi Zuo and Sen Zhao and Robert Blank and Davut Pehlivan and Shuangshuang Dong and Jianguo Zhang and Jianxiong Shen and Nuo Si and Yipeng Wang and Gang Liu and Shugang Li and Yanxue Zhao and Hong Zhao and Yixin Chen and Yu Zhao and Xiaofei Song and Jianhua Hu and Mao Lin and Ye Tian and Bo Yuan and Keyi Yu and Yuchen Niu and Bin Yu and Xiaoxin Li and Jia Chen and Zihui Yan and Qiankun Zhu and Xiaolu Meng and Xiaoli Chen and Jianzhong Su and Xiuli Zhao and Xiaoyue Wang and Yue Ming and Xiao Li and Raggio, {Cathleen L.} and Baozhong Zhang and Xisheng Weng and Shuyang Zhang and Morio Matsumoto",
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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 - Zhang, Shuyang

AU - Matsumoto, Morio

PY - 2019/1/1

Y1 - 2019/1/1

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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