Funding

Medical Research Council (MRC) National Mouse Genetics Network. “Congenital Anomalies: Patient-led Functional Genomics”. Cluster role: Oxford lead and clinical interface coordinator. https://nmgn.mrc.ukri.org

NIH, USA R01. “Molecular and cellular basis of craniosynostosis”. Role: Co-I, with Prof Gage Crump (PI, USC).

Medical Research Council (MRC). “Uncovering new mechanisms of craniosynostosis associated with structural and copy number variation, using mouse modelling and human neural crest cells”. Role: Co-I, with Prof Andrew Wilkie (PI).

Action Medical Research Project Grant from 2016-2019.

Growth of the skull vault is closely coordinated with expansion of the underlying brain and primarily occurs at cranial sutures. These are the narrow strips of fibrous mesenchyme separating the flat bones of the skull vault that contain a population of cells with the capacity to respond to changes in brain volume and control bone deposition at the sutural margins. Sutures fuse naturally after full brain size is achieved, but in approximately 1 in 2,000 children fusion occurs prematurely during fetal development or infancy. This is called craniosynostosis and it has potentially serious consequences for brain development and can lead to problems with vision, hearing, breathing and dentition. To understand why this happens our approach has been to identify underlying genetic causes. As well as providing invaluable information for patients and families, this has shed light on the embryological processes important for cranial suture development.

Ongoing research

Cranial suture development

We do not fully understand biogenesis of cranial sutures, nor the mechanisms that translate transduction from mechanical stretch of the expanding brain to growth and maintenance of sutural patency. To explore this we are using single cell transcriptomics of cranial sutures, combined with analysis of craniosynostosis models generated using CRISPR/Cas9-based gene targeting.

Identification of non-coding mutations in craniosynostosis

There are many craniosynostosis patients, who have a potential genetic origin, but for whom we are not yet able to define a causative  variant. It may be that the causes lie in non-coding DNA - regions not routinely analysed in genetic diagnosis. To identify non-coding mutations our approach is to map regulatory elements (RE) that control the expression of genes involved in suture development and maintenance, and intersect this information with sequence data obtained from patients. This work was supported by Action Medical Research .