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

Vikram P Sharma, Aimée L Fenwick, Mia S Brockop, Simon J McGowan, Jacqueline A C 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 JohnsonSteven A Wall, Peter J van der Spek, Irene M J Mathijssen, Robert E Maxson, Stephen R F Twigg, Andrew O M Wilkie, WGS Consortium

Research output: Contribution to journalArticlepeer-review

131 Citations (Scopus)


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. 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.

Original languageEnglish
Pages (from-to)304-7
Number of pages4
JournalNature Genetics
Issue number3
Publication statusPublished - Mar 2013
Externally publishedYes


  • Acrocephalosyndactylia
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cranial Sutures
  • Craniosynostoses
  • Dimerization
  • Exome
  • Gene Expression Regulation, Developmental
  • Heterozygote
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins
  • Sequence Analysis, DNA
  • Transcriptional Activation
  • Twist Transcription Factor


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