PhD; BSc (Hons)
My research focuses on identifying new causes of craniosynostosis by examining non-coding regions in the genome. Craniosynostosis, the premature fusion of the cranial sutures, is a serious disorder with a prevalence of 1 in 2,000-2,500. Genetic causes are associated with an increased frequency of complications, often leading to long-term health problems. Despite recent successes in identifying new genetic causes, a significant proportion of patients (~60% of individuals analysed by exome or whole genome sequencing) remain undiagnosed. One potential explanation is that some causative variants lie in non-coding DNA, in regions not routinely analysed in NGS data. Active regulatory elements are identified by looking at genome-wide enrichments of histone K27ac and K4me1 (enhancer) or K4me3 (promoter), using ChIP-Seq approach in human and murine embryonic suture materials. In addition, ATAC and DNase-Seq are also applied on suture-derived cells, to query the location of open chromatin as well as the binding of transcription factors over the regulatory elements. Targeted resequencing and whole genome sequencing are used to profile alternations of DNA sequences in undiagnosed patient cohort. Possible causative variants are subsequently denoted by superimposing locations of regulatory elements over the list of sequence variants. These genetics discoveries can then be understood by integrating the information with multiple approaches from chromatin higher-order structures study, cell and development biology and mouse genetics.
This research will lead to a better understanding of craniosynostosis as well as cranial suture development. It will hopefully provide a clearer prognosis for patients and families and end their journey of diagnosis which may have lasted for years or decades.
Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism.
Twigg SRF. et al, (2016), Clin genet, 90, 270 - 275
A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.
Twigg SRF. et al, (2016), Am j hum genet, 98, 1256 - 1265