{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/366665"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/366665","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Hampstead, Juliet"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Hurles, Matthew"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-10-01","date_published":"2023-10-01","updated_at":"2026-07-22T22:24:16Z","subjects":["Developmental disorders","Genetics","Methylation","Methylation signatures"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4aa118a7-0a20-46e3-84e6-3ccf9519eb0d/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.107502","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Hurles, Matthew"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Wellcome Sanger Institute, Hinxton, UK"]},{"key":"dc:creator","label":"Author","values":["Hampstead, Juliet"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2023-10-01"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/366665"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Developmental disorders","Genetics","Methylation","Methylation signatures"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4aa118a7-0a20-46e3-84e6-3ccf9519eb0d/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.107502"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e196163c-3489-4f81-b8d9-82143b69a537/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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. 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