Master of Science
Pathology and Laboratory Medicine
London Health Sciences Center, Verspeeten Genome Center
ABSTRACT: Diagnosis for neurodevelopmental disorders poses numerous challenges, related to the lack of specific findings and limited understanding of clinical impact of the majority of genetic variation. Epigenomics mechanisms involve chemical modifications in DNA that involve a range of cellular mechanisms. DNA methylation is an epigenetic mechanism involving addition and removal of methyl groups to cytosine residues. These methylation signals form episignatures; patterns of methylation that can be used as biomarkers capable of differentiating neurodevelopmental disorders. EpiSigns have enabled molecular diagnosis of a number of genetic conditions, classification of variants of unknown significance, and provided insights into the pathophysiology of neurodevelopmental disorders. I hypothesized DNA methylation can provide classifications of neurodevelopmental disorders, and identify epigenetic patterns that relate the phenotypic and genotypic variations seen in these patients. Main objectives of this work include 1) determination of syndrome specific episignatures, 2) analysis of domain specific variants and their effects on the methylation profiles and ensuing phenotypes 3) determine effectiveness of episignature assessment in classifying neurodevelopmental disorders in paralogous genes, 4) assessing phenotypic overlap between distinct neurodevelopmental disorders and correlation to their methylation profiles. My thesis demonstrates that these episignatures are robust biomarkers that inform effective methods to diagnose complex neurodevelopmental disorders, and provide evidence of shared functional pathways highlighted by the various genomic and phenotypic contexts episignatures have been derived from.
Summary for Lay Audience
Within each cell, genetics acts as a blueprint to provide instructions for the creation and maintenance of various cellular structures and functions, however, given how this genetic blueprint is identical across all cells in an organism, additional methods of control must exist. While the blueprint remains the same, different levels of expression of genes within the genome allow for differentiation, resulting in the various different types of cells available in the human body. Additionally, cells can change over time, at different developmental periods, where particular genes are expressed, and eventually turned off when their function is complete. The study of this phenomenon, where the genome is not altered, but instead has the expression of different regions turned on and off, is referred to as epigenetics. One method for this type of epigenetic change is DNA methylation, a chemical mark that can be attached to parts of the genome that changes how genes at that region of the genome are expressed, similar to an on/off switch. When defects in the genome or epigenome occur, disorder of the cell’s control systems is caused, and disease ensues, as switches supposed to remain off are switched on, or vice versa. This thesis works to observe how they differ from persons with disease compared to those without them, to create episignatures, chemical fingerprints of gene defects. In particular I have assessed DNA methylation in relation to neurodevelopmental disorders, syndromes that present with a complex set of characteristics related to intellectual development, and cognitive abilities. By cataloging and describing the genome of persons with neurodevelopmental disorders, we can identify which on/off switches are in disarray compared to their healthy counterparts, helping to better understand the ways in which these disorders present themselves, and provide ways to identify them in new persons.
Reilly, John, "Identification of DNA Methylation Episignatures for Classification and Phenotype/Genotype Correlation in Mendelian Neurodevelopmental Disorders" (2022). Electronic Thesis and Dissertation Repository. 8537.