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Genet Med. 2019 Jan 14. doi: 10.1038/s41436-018-0377-x. [Epub ahead of print]

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

Author information

1
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
2
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
3
Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
4
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. dr.wunan@pumch.cn.
5
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China. dr.wunan@pumch.cn.
6
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China. dr.wunan@pumch.cn.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. dr.wunan@pumch.cn.
8
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
9
NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai, China.
10
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
11
Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
12
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
13
Graduate School of Peking Union Medical College, Beijing, China.
14
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
15
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China.
16
Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
17
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
18
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
19
The McKusick-Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
20
The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
21
Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
22
Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China.
23
College of Biomedical Engineering, The Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
24
PET-CT Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
25
Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
26
Department of Orthopedic Surgery, Hospital for Special Surgery, New York, NY, USA.
27
Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
28
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
29
Harvard Medical School, Boston, MA, USA.
30
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
31
Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.
32
Baylor Genetics Laboratory, Houston, TX, USA.
33
Departments of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
34
Texas Children's Hospital, Houston, TX, USA.
35
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. qiuguixingpumch@126.com.
36
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China. qiuguixingpumch@126.com.
37
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China. qiuguixingpumch@126.com.

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

PMID:
30636772
DOI:
10.1038/s41436-018-0377-x

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