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

Michael A Levy, Raissa Relator, Haley McConkey, Erinija Pranckeviciene, Jennifer Kerkhof, Mouna Barat-Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R DuPont, Mariet W Elting, Laurence Faivre, Timothy Fee, Marco Ferilli, Robin S Fletcher, Florian Cherick, Aidin ForoutanMichael J Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J Louie, Silvia Maitz, Donatella Milani, Angela T Morgan, Renske Oegema, Elsebet Østergaard, Nathalie Ruiz Pallares, Maria Piccione, Astrid S Plomp, Cathryn Poulton, Jack Reilly, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W E Santen, Fernando Santos-Simarro, Josephine Schijns, Gabriella Maria Squeo, Miya St John, Christel Thauvin-Robinet, Giovanna Traficante, Pleuntje J van der Sluijs, Samantha A Vergano, Niels Vos, Kellie K Walden, Dimitar Azmanov, Tugce B Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A Lee, Marcel M A M Mannens, Tony Roscioli, Victoria Siu, David J Amor, Gareth Baynam, Eric G Bend, Kym Boycott, Nicola Brunetti-Pierri, Philippe M Campeau, Dominique Campion, John Christodoulou, David Dyment, Natacha Esber, Jill A Fahrner, Mark D Fleming, David Genevieve, Delphine Heron, Thomas Husson, Kristin D Kernohan, Alisdair McNeill, Leonie A Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman-Greenberg, Charles Schwartz, Steven A Skinner, Roger E Stevenson, Marie Vincent, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L Tedder, Bekim Sadikovic

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)1609-1628
Number of pages20
JournalHuman mutation
Issue number11
Early online date29 Jul 2022
Publication statusPublished - Nov 2022


  • DNA methylation
  • clinical diagnostics
  • episignatures
  • neurodevelopmental syndromes


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