Functional genomics of developmental disorders

Abstract

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.