Molecular Genetics of Craniosynostosis


Craniosynostosis (CS) is a relatively prevalent congenital malformation, due to the premature ossification of calvarial sutures that articulate skull bones, leading to a variable alteration of craniofacial landmarks and shape. CS is extremely heterogeneous in both clinical and a etiological aspects. It occurs as an isolated defect (i.e. nonsyndromic) in most cases, while it is syndromic in less than one fourth of cases. A genetic aetiology (i.e. mutations in FGFR, TWIST1, EFNB1, MSX, and ERF genes, among others) is known for most syndromes. Recent studies helped clarifying the genetic basis of new CS syndromes and nonsyndromic forms. The discovery of new genes (including RUNX2, ALX4, TCF12 and ZIC1) enabled deciphering the complex signalling network that orchestrates craniofacial development. In this light, the entire CS disease spectrum can be regarded as a nosological continuum, with variable degree of severity, in which a strong genetic component provides the background for environmental factors that contribute to the aetiopathogenesis of the birth defect.

Key Concepts

  • Craniosynostosis is a frequent congenital defect with a high degree of clinical and genetic heterogeneity.
  • Nonsyndromic forms are more frequent, although their aetiology is still poorly understood.
  • Many developmental syndromes include craniosynostosis in their phenotype.
  • Different closely interacting genes (FGFR, TWIST1, MSX2, ERF, TCF12, among others) are involved in the molecular genetics of the best characterised and more frequent syndromic craniosynostoses.
  • Most genes involved in the etiopathogenesis of craniosynostosis interact within a common gene network.

Keywords: craniosynostosis; sutures; FGFR; TWIST1; TCF12; ERF; MSX2; Eph‐ephrin; neural crest; craniofacial development

Figure 1. Craniosynostosis gene network. The diagram shows the network of known and predicted interactions among genes associated to CS phenotypes and syndromes (listed in Table). The network was drawn using String (version 10.0) license‐free software (http://string‐ Colored nodes refer to gene/protein symbol included in the query; small nodes are for proteins with unknown 3D structure while large nodes are for those with known structures. Edges among nodes represent interactions: known interactions are in purple (experimental evidence) or light blue (data gathered from curated datasets); light green edges indicate interactions inferred from text‐mining in scientific literature. Functional annotations of the entire gene set, according to Gene Ontology (GO) consortium specifications, are provided in the table on the right.


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Further Reading

Heuzé Y, Holmes G, Peter I, Richtsmeier JT and Jabs EW (2014) Closing the gap: genetic and genomic continuum from syndromic to nonsyndromic craniosynostoses. Current Genetic Medicine Reports 2 (3): 135–145.

Twigg SR and Wilkie AO (2015a) A genetic‐pathophysiological framework for craniosynostosis. American Journal of Human Genetics 97 (3): 359–377. DOI: 10.1016/j.ajhg.2015.07.006.

Twigg SR and Wilkie AO (2015b) New insights into craniofacial malformations. Human Molecular Genetics 24 (R1): R50–R59. DOI: 10.1093/hmg/ddv228. Epub 2015 Jun 17.

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Lattanzi, Wanda(Nov 2016) Molecular Genetics of Craniosynostosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025186]