Journal article

Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis

Vikram P Sharma, Aimee L Fenwick, Mia S Brockop, Simon J McGowan, Jacqueline AC Goos, A Jeannette M Hoogeboom, Angela F Brady, Nu Owase Jeelani, Sally Ann Lynch, John B Mulliken, Dylan J Murray, Julie M Phipps, Elizabeth Sweeney, Susan E Tomkins, Louise C Wilson, Sophia Bennett, Richard J Cornall, John Broxholme, Alexander Kanapin, David Johnson Show all



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 cases, 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 synostosis. 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. ..

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University of Melbourne Researchers


Awarded by US National Institutes of Health (NIH)

Awarded by Wellcome Trust

Awarded by Medical Research Council


Funding Acknowledgements

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. Fuchtbauer (Aarhus University) for constructs and Y. Zhuang (Duke University) for the gift of the Tcf12<SUP>flox</SUP> 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.).