title: DNA methylation analysis in constitutional disorders: Clinical implications of the epigenome.
abstract: Genomic, chromosomal, and gene-specific changes in the DNA sequence underpin both phenotypic variations in populations as well as disease associations, and the application of genomic technologies for the identification of constitutional (inherited) or somatic (acquired) alterations in DNA sequence forms a cornerstone of clinical and molecular genetics. In addition to the disruption of primary DNA sequence, the modulation of DNA function by epigenetic phenomena, in particular by DNA methylation, has long been known to play a role in the regulation of gene expression and consequent pathogenesis. However, these epigenetic factors have been identified only in a handful of pediatric conditions, including imprinting disorders. Technological advances in the past decade that have revolutionized clinical genomics are now rapidly being applied to the emerging discipline of clinical epigenomics. Here, we present an overview of epigenetic mechanisms with a focus on DNA modifications, including the molecular mechanisms of DNA methylation and subtypes of DNA modifications, and we describe the classic and emerging genomic technologies that are being applied to this study. This review focuses primarily on constitutional epigenomic conditions associated with a spectrum of developmental and intellectual disabilities. Epigenomic disorders are discussed in the context of global genomic disorders, imprinting disorders, and single gene disorders. We include a section focused on integration of genetic and epigenetic mechanisms together with their effect on clinical phenotypes. Finally, we summarize emerging epigenomic technologies and their impact on diagnostic aspects of constitutional genetic and epigenetic disorders.
authors.affiliation: a Departments of Pathology and Laboratory Medicine .
authors.forename: Laila C
authors.initials: LC
authors.lastname: Schenkel
authors.affiliation: b Departments of Biochemistry , Oncology and Paediatrics, Western University , London , ON , Canada .|c London Regional Cancer Program, London Health Sciences Centre , London , ON , Canada .|e Children's Health Research Institute , London , ON , Canada .
authors.forename: David I
authors.initials: DI
authors.lastname: Rodenhiser
authors.affiliation: a Departments of Pathology and Laboratory Medicine .|b Departments of Biochemistry , Oncology and Paediatrics, Western University , London , ON , Canada .|c London Regional Cancer Program, London Health Sciences Centre , London , ON , Canada .|d Molecular Genetics Laboratory, London Health Sciences Centre , London , ON , Canada .|e Children's Health Research Institute , London , ON , Canada .
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ainsworth
authors.affiliation: f Department of Pathology and Molecular Medicine , and.|g Department of Clinical Epidemiology and Biostatistics , McMaster University , Hamilton , ON , Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.affiliation: a Departments of Pathology and Laboratory Medicine .|c London Regional Cancer Program, London Health Sciences Centre , London , ON , Canada .|d Molecular Genetics Laboratory, London Health Sciences Centre , London , ON , Canada .|e Children's Health Research Institute , London , ON , Canada .
authors.forename: Bekim
authors.initials: B
authors.lastname: Sadikovic
mesh_terms: D000818:Animals; D019175:DNA Methylation / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics; D044127:Epigenesis, Genetic; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D016678:Genome; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics
keywords: Clinical genomics; DNA methylation; epigenetics; imprinting; intellectual and developmental disability