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.