Publication Date
8-6-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-50159-6
PMID
39107278
PMCID
PMC11303402
PubMedCentral® Posted Date
8-6-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, DNA Methylation, Female, Child, Male, Epilepsy, DNA Copy Number Variations, Child, Preschool, DNA-Binding Proteins, Adolescent, Genetic Testing, Infant
Abstract
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 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.
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