2026-09-22T15:03:08Zhttps://api.repository.cam.ac.uk/server/oai/request

oai:www.repository.cam.ac.uk:1810/3666652024-04-06T00:45:10Zcom_1810_224161com_1810_256067col_1810_224162

Functional genomics of developmental disorders https://doi.org/10.17863/CAM.107502 Hampstead, Juliet Hurles, Matthew DNA methylation, or the epigenetic modification of primarily cytosine bases within DNA to 5-methylcytosine through the addition of a methyl group, is an epigenetic mark with a variety of biological and cellular roles. Genetic and environmental influences can perturb DNA methylation patterns in humans, and the set of differentially methylated CpG sites perturbed can be collectively called a DNA methylation signature. In this thesis, I characterise DNA methylation signatures as a diagnostic biomarker for children with rare developmental disorders in chromatin-modifying genes. I show that DNA methylation signatures are a general property of these genes, that they have substantial clinical and diagnostic utility, and that they can be used to resolve variants of uncertain significance. I also show that these signatures are robust across scientific centres and can be generated across multiple tissues. Lastly, I compare DNA methylation signatures generated from methylation microarrays to those generated from genome-wide long read sequencing data, and provide evidence that long read sequencing is a reliable and scalable method to profile 5-methylcytosine for DNA methylation signature-based classification. Overall, my work emphasises the need for scalable, cost-effective, and relatively high-throughput biomarkers in the characterisation and diagnosis of rare developmental disorder syndromes. University of Cambridge 2023-10-01 Thesis Doctoral Doctor of Philosophy (PhD) eng Wellcome Sanger Institute, Hinxton, UK https://www.repository.cam.ac.uk/handle/1810/366665 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e196163c-3489-4f81-b8d9-82143b69a537/download 92474091fa0df3d63091d6eab7167a46 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4aa118a7-0a20-46e3-84e6-3ccf9519eb0d/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Developmental disorders Genetics Methylation Methylation signatures