Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis

Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15116-15121. doi: 10.1073/pnas.1902041116. Epub 2019 Jul 10.


Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 × 10-8); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 × 10-12). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

Keywords: TFAP2B; craniofacial syndromes; craniosynostosis; de novo mutation; pleiotropy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Craniosynostoses / diagnosis
  • Craniosynostoses / genetics*
  • Craniosynostoses / pathology
  • Exome
  • Female
  • Gene Expression
  • Glypicans / genetics*
  • Histone Acetyltransferases / genetics*
  • Humans
  • Male
  • Mutation*
  • Nuclear Proteins / genetics*
  • Pedigree
  • Risk Assessment
  • SOXC Transcription Factors / genetics*
  • Signal Transduction
  • Skull / abnormalities
  • Skull / growth & development
  • Skull / metabolism
  • Transcription Factor AP-2 / genetics*
  • Whole Exome Sequencing
  • Zinc Finger Protein Gli2 / genetics*
  • alpha Catenin / genetics*


  • CTNNA1 protein, human
  • GLI2 protein, human
  • GPC4 protein, human
  • Glypicans
  • Nuclear Proteins
  • SOX11 protein, human
  • SOXC Transcription Factors
  • TFAP2B protein, human
  • Transcription Factor AP-2
  • Zinc Finger Protein Gli2
  • alpha Catenin
  • Histone Acetyltransferases
  • KAT6A protein, human