TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model
TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model
复制标题
TBX6 相关先天性脊柱侧凸 (TACS) 作为先天性脊柱侧凸的临床可区分亚型：支持复合遗传和 TBX6 基因剂量模型的进一步证据
DOI：
10.1038/s41436-018-0377-x
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发表时间：
2019-07-01
影响因子：
8.8
通讯作者：
Ootomo, Nao
中科院分区：
文献类型：
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作者：
Liu, Jiaqi;Wu, Nan;Ootomo, Nao
方法对来自中国(N= 345，队列1)、日本(N= 142，队列2)和美国(N=10，队列3)的先天性脊柱侧弯(CS)患者进行研究。根据TBX6基因分型比较临床可测的内表型。用微型计算机断层扫描(Micro-CT)技术研究了Tbx6化合物遗传小鼠模型(N= 52)。结果在队列1中，TACS患者(N= 33)的发病年龄显著低于其余CS患者(P= 0.02)，表现为一个或多个半椎体/蝴蝶椎体(P= 4.9 × 10-8)，并表现为脊柱下部畸形(T8-S5，P= 4.4 × 10-3)；两个重复队列中的观察结果得到证实。单纯性肋骨畸形多见于TACS患者(P=3.1 × 10-7)，椎管内异常少见(P=7.0×10-7)。临床使用的TACScore曲线下面积(AUC)为0.9(P=1.6×10-15)。ATbx6-/mh小鼠模型支持Tacs表型的基因剂量效应。结论TACS是一个临床可区分的实体，具有一致的临床可测量内表型。Tbx6/Tbx6复合遗传中脊柱异常的类型和分布表明，作为脊柱发育出生缺陷的原因，基因剂量存在微妙的扰动，约占CS的10%。
PurposeTo characterize clinically measurable endophenotypes, implicating theTBX6compound inheritance model.MethodsPatients 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 theTBX6genotypes. A mouse model forTbx6compound inheritance (N= 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition ofTBX6-associated CS (TACS).ResultsIn 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). ATbx6-/mh (mild-hypomorphic)mouse model supported that a gene dosage effect underlies the TACS phenotype.ConclusionTACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities inTBX6/Tbx6compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.