Human mutation · 2022

Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.

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Levy Michael A, Relator Raissa, McConkey Haley, Pranckeviciene Erinija, Kerkhof Jennifer, Barat-Houari Mouna, Bargiacchi Sara, Biamino Elisa, Palomares Bralo María, 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 R, 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 M, 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

Аннотация

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 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.

Предметные рубрики MeSH

CpG Islands DNA Methylation DNA, Intergenic Epigenesis, Genetic Humans Neurodevelopmental Disorders Syndrome

Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.

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Аннотация

Предметные рубрики MeSH