Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement
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Published:2024-08-06
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
LaFlamme Christy W.ORCID, Rastin CassandraORCID, Sengupta Soham, Pennington Helen E.ORCID, Russ-Hall Sophie J.ORCID, Schneider Amy L.ORCID, Bonkowski Emily S., Almanza Fuerte Edith P., Allan Talia J.ORCID, Zalusky Miranda Perez-GaleyORCID, Goffena JoyORCID, Gibson Sophia B.ORCID, Nyaga Denis M.ORCID, Lieffering Nico, Hebbar Malavika, Walker Emily V.ORCID, Darnell Daniel, Olsen Scott R., Kolekar PandurangORCID, Djekidel Mohamed Nadhir, Rosikiewicz WojciechORCID, McConkey Haley, Kerkhof JenniferORCID, Levy Michael A., Relator Raissa, Lev Dorit, Lerman-Sagie Tally, Park Kristen L.ORCID, Alders MarielleORCID, Cappuccio Gerarda, Chatron NicolasORCID, Demain Leigh, Genevieve DavidORCID, Lesca GaetanORCID, Roscioli TonyORCID, Sanlaville Damien, Tedder Matthew L., Gupta Sachin, Jones Elizabeth A., Weisz-Hubshman Monika, Ketkar Shamika, Dai Hongzheng, Worley Kim C.ORCID, Rosenfeld Jill A.ORCID, Chao Hsiao-TuanORCID, , Neale GeoffreyORCID, Carvill Gemma L.ORCID, , Wang ZhaomingORCID, Berkovic Samuel F.ORCID, Sadleir Lynette G., Miller Danny E., Scheffer Ingrid E., Sadikovic BekimORCID, Mefford Heather C.ORCID
Abstract
AbstractSequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.
Funder
Citizens United for Research in Epilepsy
Publisher
Springer Science and Business Media LLC
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1. Developmental and epileptic encephalopathies;Nature Reviews Disease Primers;2024-09-05
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