Journal
GENETICS IN MEDICINE
Volume 21, Issue 7, Pages 1548-1558Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-018-0377-x
Keywords
congenital scoliosis (CS); 16p11.2/TBX6; compound inheritance model; genotype-phenotype correlation; gene dosage
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Funding
- National Natural Science Foundation of China [81822030, 81501852, 81472045, 81772301, 31625015, 31571297, 31771396, 81472046, 81772299, 31521003, 81672123, 7162029]
- Beijing Natural Science Foundation [7162029, 7172175]
- Beijing Nova Program [Z161100004916123]
- Beijing Nova Program Interdisciplinary Collaborative Project [xxjc201717]
- 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine
- Central Level Public Interest Program for Scientific Research Institute [2016ZX310177]
- Fundamental Research Funds for the Central Universities [3332016006]
- Chinese Academy of Medical Sciences (CAMS) Initiative Fund for Medical Sciences [2016-I2M-3-003, 2016-I2M-2-006, 2017-I2M-2-001]
- Distinguished Youth Foundation of Peking Union Medical College Hospital [JQ201506]
- PUMCH Science Fund for Junior Faculty [PUMCH-2016-1.1]
- National Key Research and Development Program of China [2016YFC0901501]
- Japan Agency for Medical Research and Development (AMED) [17ek0109280h0001, 17824969]
- Japan Orthopedics and Traumatology Research Foundation [358]
- US National Institutes of Health, National Institute of Neurological Disorders and Stroke [NINDS R01 NS058529, R35 NS105078]
- National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]
- National Human Genome Research Institute [NHGRI K08 HG008986]
- PUMC Youth Fund
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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 x 10(-8)), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 x 10(-3)); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TAGS patients (P = 3.1 x 10(-7)), while intraspinal anomalies were uncommon (P = 7.0 x 10(-7)). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 x 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.
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