Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders
Levy, Michael A; Relator, Raissa; McConkey, Haley; Pranckeviciene, Erinija; Kerkhof, Jennifer; Barat-Houari, Mouna; Bargiacchi, Sara; Biamino, Elisa; Bralo, María Palomares; Cappuccio, Gerarda; Ciolfi, Andrea; Clarke, Angus; DuPont, Barbara R; Elting, Mariet W; Faivre, Laurence; Fee, Timothy; Ferilli, Marco; Fletcher, Robin S; Cherick, Florian; Foroutan, Aidin; Friez, Michael J; Gervasini, Cristina; Haghshenas, Sadegheh; Hilton, Benjamin A; Jenkins, Zandra; Kaur, Simranpreet; Lewis, Suzanne; Louie, Raymond J; Maitz, Silvia; Milani, Donatella; Morgan, Angela T; Oegema, Renske; Østergaard, Elsebet; Pallares, Nathalie Ruiz; Piccione, Maria; Plomp, Astrid S; Poulton, Cathryn; Reilly, Jack; Rius, Rocio; Robertson, Stephen; Rooney, Kathleen; Rousseau, Justine; Santen, Gijs W E; Santos-Simarro, Fernando; Schijns, Josephine; Squeo, Gabriella Maria; John, Miya St; Thauvin-Robinet, Christel; Traficante, Giovanna; van der Sluijs, Pleuntje J; Vergano, Samantha A; Vos, Niels; Walden, Kellie K; Azmanov, Dimitar; Balci, Tugce B; Banka, Siddharth; Gecz, Jozef; Henneman, Peter; Lee, Jennifer A; Mannens, Marcel M A M; Roscioli, Tony; Siu, Victoria; Amor, David J; Baynam, Gareth; Bend, Eric G; Boycott, Kym; Brunetti-Pierri, Nicola; Campeau, Philippe M; Campion, Dominique; Christodoulou, John; Dyment, David; Esber, Natacha; Fahrner, Jill A; Fleming, Mark D; Genevieve, David; Heron, Delphine; Husson, Thomas; Kernohan, Kristin D; McNeill, Alisdair; Menke, Leonie A; Merla, Giuseppe; Prontera, Paolo; Rockman-Greenberg, Cheryl; Schwartz, Charles; Skinner, Steven A; Stevenson, Roger E; Vincent, Marie; Vitobello, Antonio; Tartaglia, Marco; Alders, Marielle; Tedder, Matthew L; Sadikovic, Bekim
(2022) Human mutation, volume 43, issue 11, pp. 1609 - 1628
(Article)
Abstract
An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which
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can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.
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Keywords: DNA methylation, clinical diagnostics, episignatures, neurodevelopmental syndromes, Genetics(clinical), Genetics, Journal Article
ISSN: 1059-7794
Publisher: Wiley-Liss Inc.
Note: Funding Information: Funding for this study was provided in part by the London Health Sciences Molecular Diagnostics Development Fund. This work was funded by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI‐188) The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to JC is generously supported by The Royal Children's Hospital Foundation. Funding was provided in part from the Italian Ministry of Health (5 × 1000, CCR‐2017‐23669081 and RCR‐2020‐23670068_001, to M. T.) and the Italian Ministry of Research (FOE 2019, to M. T.). Funding was provided in part by a grant from the South Carolina Department of Disabilities and Special Needs. In memory of Ethan Francis Schwartz, 1996–1998. Publisher Copyright: © 2022 Wiley Periodicals LLC.
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