Project: PRJNA1121606
Sequence-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 850K 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. Overall design: We performed Illumina DNA Methylation Array (EPIC 850K V1) on peripheral blood-derived DNA samples for individuals with genetically unresolved Developmental and Epileptic Encephalopathies (DEEs) in order to determine potential causal etiologies. We also investigated a subset of individuals with pathogenic variants in CHD2. All samples in GSE269416 are derived from peripheral blood DNA, except for 207179240107_R06C01 (saliva), 207179240107_R08C01 (saliva), and 205707890075_R05C01 (fibroblast).