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



To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model.


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).


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.


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.

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We thank all the individuals, families, and physicians involved in the study for their participation. We thank the nurses from the Department of Orthopedic Surgery at Peking Union Medical College Hospital for assistance with patient enrollment. We thank the members of Japan Early Onset Scoliosis Research Group: Noriaki Kawakami, Toshiaki Kotani, Hideki Sudo, Ikuho Yonezawa, Koki Uno, Hiroshi Taneichi, Kei Watanabe, Shohei Minami, Hideki Shigematsu, Ryo Sugawara, Yuki Taniguchi, and Nao Ootomo. We thank Sally Dunwoodie and Gavin Chapman from Victor Chang Cardiac Research Institute for their collaborations. We appreciate the support of Ellen Wald at the University of Wisconsin–Madison. This research was funded in part by the National Natural Science Foundation of China (81822030 and 81501852 to N.W., 81472045 and 81772301 to G.Q., 31625015, 31571297 and 31771396 to F.Z., 81472046 and 81772299 to Z.W., 31521003 to L.J., 81672123 to J.Z., 7162029 to X.C.), Beijing Natural Science Foundation (7172175 to N.W., 7162029 to X.C.), Beijing Nova Program (Z161100004916123 to N.W.), Beijing Nova Program Interdisciplinary Collaborative Project (xxjc201717 to N.W.), 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine (to N.W.), the Central Level Public Interest Program for Scientific Research Institute (2016ZX310177 to N.W.), PUMC Youth Fund & the Fundamental Research Funds for the Central Universities (3332016006 to N.W.), Chinese Academy of Medical Sciences (CAMS) Initiative Fund for Medical Sciences (2016-I2M-3-003 to G.Q. and N.W., 2016-I2M-2-006 and 2017-I2M-2-001 to Z.W.), the Distinguished Youth Foundation of Peking Union Medical College Hospital (JQ201506 to N.W.), the 2016 PUMCH Science Fund for Junior Faculty (PUMCH-2016-1.1 to N.W.), and the National Key Research and Development Program of China (no. 2016YFC0901501 to S.Z.). This work was also supported by the Japan Agency for Medical Research and Development (AMED, number 17ek0109280h0001 and 17824969 to S.I.) and Japan Orthopedics and Traumatology Research Foundation (number 358 to K.T.), and the US National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS R01 NS058529 and R35 NS105078 to J.R.L.), National Human Genome Research Institute/National Heart, Lung, and Blood Institute (NHGRI/NHLBI UM1 HG006542 to D.V. and J.R.L.), and the National Human Genome Research Institute (NHGRI K08 HG008986 to J.E.P.).

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Correspondence to Nan Wu MD or Guixing Qiu MD.

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J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Genetics Laboratory (http://bmgl.com). The other authors declare no conflicts of interest.

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These authors share senior authorship: Zhihong Wu, Shiro Ikegawa, James R. Lupski, Feng Zhang, Guixing Qiu.

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

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