Exome and whole genome sequencing to identify new genetic causes of skull malformations

Supervisors:  Prof Andrew Wilkie and Dr Steve Twigg

Brief description
Massively parallel genome sequencing has revolutionised the identification of Mendelian disease genes. This project will apply this approach to craniosynostosis, the premature fusion of the sutures of the skull.1,2. Oxford is one of 4 national referral centres for this condition, which has a prevalence of 1 in 2,250; we have one of the best characterised sample collections internationally, and we have a proven track record of success having identified and published more novel disease genes (MEGF8, TCF12, ERF, ZIC1, SMO, CDC45, IL6ST and several others still undergoing investigation) than any other group working on this group of diseases. The UK’s Genomics England 100,000 Genomes project (https://www.genomicsengland.co.uk) with which we are closely involved, will provide further opportunities for discovery during the course of the studentship.

To identify new human disease genes in craniosynostosis and other craniofacial malformations and understand their associated clinical features and pathophysiology

Training opportunities
You will be able to follow through the entire experimental process from choice of DNA sample to identification of a new disease gene. On the way you will learn how DNA is processed for whole exome capture and massively parallel sequencing and how the raw sequence is filtered. For the sequence variants remaining you will use a combination of bioinformatics tools, biological knowledge and analysis of the literature to identify the most likely candidate changes. You will then verify these in the original samples and, for the best candidate mutations, analyse the DNA sequence of a large number of independent samples to seek independent mutations. Success in this venture would lead to further molecular analysis of pathophysiology of the mutations using approaches tailored to the biological problem, potentially including modelling in mice. References 3-8 below provide examples of the types of experimental approach undertaken, tailored to the gene and mutations identified.

Further reading:

  1. Johnson D & Wilkie AOM (2011). Craniosynostosis. Eur J Hum Genet 19:369-376.
  2. Twigg, SRF & Wilkie AOM (2015). A genetic-pathophysiological framework for craniosynostosis. Am J Hum Genet 97:359-77.
  3. Twigg SRF, et al. (2012). Mutations in the multidomain protein MEGF8 identify a new subtype of Carpenter syndrome associated with defective lateralization. Am J Hum Genet 91:897-905.
  4. Sharma VP, et al. (2013). Mutations of TCF12, encoding a basic-helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nature Genet 45:304-307.
  5. Twigg SRF, et al. (2013). Reduced dosage of ERF causes complex craniosynostosis in humans and mice, and links ERK1/2 signalling to regulation of osteogenesis. Nature Genet 45:308-313.
  6. Twigg SRF, et al. (2015). Gain-of-function mutations in ZIC1 are associated with coronal craniosynostosis and learning disability. Am J Hum Genet 97:378-388.
  7. Twigg SRF, et al. (2016). A recurrent mosaic mutation of SMO, encoding the hedgehog signal transducer Smoothened, is the major cause of Curry-Jones syndrome. Am J Hum Genet 98:1256-1265.
  8. Fenwick AL, et al. (2016). Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. Am J Hum Genet 99:125-138.

For further information, please contact Prof Andrew Wilkie or Dr Steve Twigg