报告题目：Molecular Genetic Testing and the Future of Clinical Genetic Diagnosis for Rare Diseases
报告人： 周岩 博士（牛津大学Weatherall 分子医学研究所）
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 and cranial suture development. It would also provide a clearer prognosis for patients and families and end their journey of diagnosis which may have lasted for years or decades.