Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ∼21% of cases3, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis4,5,6. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development.
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NCBI Reference Sequence
Protein Data Bank
We thank all the families for their participation, S. Butler for cell culture, J. Frankland and T. Rostron for DNA sequencing, S. Knight for coordinating array–comparative genomic hybridization (aCGH), L. Gregory and the High-Throughput Genomics core at the Wellcome Trust Centre for Human Genetics for exome sequencing, R. Evans for review of anesthetic records, W. Baggley for clinical photography, A. van den Ouweland for genetic testing, E.-M. Füchtbauer (Aarhus University) for constructs and Y. Zhuang (Duke University) for the gift of the Tcf12flox mutant. This work was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre Oxford (V.P.S. and R.J.C.), the Oxford University Clinical Academic Graduate School and the Oxfordshire Health Services Research Committee (V.P.S.), the Oxford Craniofacial Unit Charitable Fund (V.P.S.), the Thames Valley Comprehensive Local Research Network (J.M.P.), The Dutch Center for Translational Molecular Medicine (P.J.v.d.S.), the Carolien Bijl Foundation (J.A.C.G.), the US National Institutes of Health (NIH; R01DE016320 and R01DE019650 to R.E.M.) and the Wellcome Trust (093329 to S.R.F.T. and A.O.M.W.).
Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–6