Identification of DNA Methylation Episignatures for Classification and Phenotype/Genotype Correlation in Mendelian Neurodevelopmental Disorders
Abstract
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.