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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). 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.
Fig. 1 Workflow for TBX6-associated congenital scoliosis (TACS) study participants in the multicenter cohorts and the animal model genotype-phenotype analyses. The discovery set (cohort 1) consisted of 345 unrelated Chinese patients with sporadic CS. The status of the TBX6 variants was screened, and the clinical characteristics were reviewed and compared according to the TBX6 genotypes, including vertebral, rib, and intraspinal anomalies. To recapitulate and investigate the phenotypic consequences of the compound inheritance and TBX6/Tbx6 gene dosage genetic model, a mouse strain with a specific combination of Tbx6 alleles was constructed. Tbx6 alleles were individually engineered and a mouse strain for the compound inheritance model was constructed by mating, introducing a truncated allele in trans with a mild hypomorphic (mh) allele, Tbx6-/mh. Furthermore, the TBX6-associated CS score (TACScore) was developed to guide and increase the efficiency of diagnosing TACS from clinically observed endophenotypes.
Fig. 2 Comparison of the distribution regarding abnormal vertebrae in non-TACS and TACS patients and in Tbx6-/mh mouse compound inheritance and gene dosage model. The x-axis shows the frequency of each malformation in each vertebra and the y-axis shows the vertebral distribution in the spine. The vertebral malformations in the non-TACS group (N = 298) were normally distributed. There were 58 TACS patients in total in three worldwide cohorts (cohort 1 from Peking Union Medical College Hospital [PUMCH] in China, N = 33; cohort 2 from the multiple centers in Japan, N =15; cohort 3 from multiple centers in the USA, N = 10). The Tbx6-/mh engineered mice (N = 52) exhibited a distinct phenotype, namely, a defect of formation involving the lower part of the spine. In addition, malformations in the upper and middle thoracic spine were significantly less involved (P = 7.3 × 10‒5 and 3.0 × 10‒6, respectively) in the TACS group than in the non-TACS group.
Fig. 3 Development and validation of the risk prediction model and diagnostic pipeline of TACS. a TACScore: risk predictive model for TACS. The final multivariate risk model was developed through a binary logistic regression analysis of detailed phenotypic data from Cohort 1. b The predictive efficacy of the TACScore. The x-axis shows the spectrum of TACScore and y-axis shows the predicted TACS frequency and the percentage of TACS patients in all CS patients with each calculated score in cohort 1 and cohort 2. The TACScore presented excellent predictive efficacy by comparing the predicted TACS risk with the real TACS frequency. The cutoff point was selected as 3 to achieve the highest accuracy. c Receiver operating characteristic (ROC) curve for the TACScore in cohort 1 and cohort 2. Areas under the curve (AUCs) were 0.9 (P = 1.6 × 10‒15; 95% CI, 0.9–1.0) for the discovery cohort (cohort 1) and 0.8 (P = 1.5 × 10−4; 95% CI, 0.7–0.9) for the validation cohort (cohort 2). d A proposed guideline for predicting and evaluating TACS. The risk of TACS evaluated by TACScore is suggested to perform prior to genetic testing. After the detection of TACS, a systemic evaluation with early interventions and genetic consultation were recommended.