Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature
Author:
LaFlamme Christy W.ORCID, Rastin Cassandra, Sengupta SohamORCID, Pennington Helen E.ORCID, Russ-Hall Sophie J., Schneider Amy L., Bonkowski Emily S.ORCID, Almanza Fuerte Edith P.ORCID, Galey Miranda, Goffena Joy, Gibson Sophia B.ORCID, Allan Talia J.ORCID, Nyaga Denis M.ORCID, Lieffering Nico, Hebbar MalavikaORCID, Walker Emily V.ORCID, Darnell DanielORCID, Olsen Scott R., Kolekar PandurangORCID, Djekidel NahdirORCID, Rosikiewicz Wojciech, McConkey Haley, Kerkhof Jennifer, Levy Michael A., Relator Raissa, Lev Dorit, Lerman-Sagie TallyORCID, Park Kristen L.ORCID, Alders MarielleORCID, Cappuccio GerardaORCID, Chatron NicolasORCID, Demain Leigh, Genevieve DavidORCID, Lesca GaetanORCID, Roscioli Tony, Sanlaville DamienORCID, Tedder Matthew L., Hubshman Monika WeiszORCID, Ketkar ShamikaORCID, Dai Hongzheng, Worley Kim CarlyleORCID, Rosenfeld Jill A.ORCID, Chao Hsiao-TuanORCID, Neale GeoffreyORCID, Carvill Gemma L.ORCID, Wang Zhaoming, Berkovic Samuel F.ORCID, Sadleir Lynette G.ORCID, Miller Danny E.ORCID, Scheffer Ingrid E.ORCID, Sadikovic Bekim, Mefford Heather C.ORCID, ,
Abstract
ABSTRACTSequence-based genetic testing currently identifies causative genetic 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. Rare epigenetic variations (“epivariants”) can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct “episignature” biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature forCHD2using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights intoCHD2pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.
Publisher
Cold Spring Harbor Laboratory
|
|