Epigenetic approaches to epilepsy diagnosis

ICNC2024
Symposia: The Impact of Genetics In The Care of Patients With Rare Pediatric Epilepsies: Past, Present Future

Epigenetic approaches to epilepsy diagnosis
Heather Mefford

Around 50% of patients with DEEs do not have a known genetic cause. To determine the molecular cause(s) of unsolved DEE, we must examine genetic variants that are beyond the capabilities of current sequencing approaches. DNA methylation is an epigenetic modification of DNA that plays a role in X-chromosome inactivation, imprinting, and regulation of gene expression, and aberrant methylation is found in neurodevelopmental disorders such as Angelman, Prader-Willi, and Fragile X syndromes. Often, rare differentially methylated regions (DMRs) are due to underlying DNA-sequence variations (e.g., GC-rich repeat expansions) that are not detected by standard sequencing technologies. Methylation patterns can also serve as biomarkers of disease; the diagnostic test EpiSign evaluates genome-wide methylation signatures for about 120 monogenic neurodevelopmental disorders (i.e. disorders caused by a single-gene variant), including more than 30 epilepsy syndromes and DEE. To investigate the role of methylation in DEE, we are generating genome-wide methylation data for a large cohort of unsolved patients to identify rare DMRs and methylation signatures. We are validating rare DMRs with long-read sequencing approaches and investigating the effect of DMRs on gene expression using engineered and patient-derived cells. Using the approach, we have identified novel candidate etiologies for DEE.

Other Lectures in this symposium
Mosaic variants detectable in blood extend the clinico-genetic spectrum of GLI3-related Hypothalamic Hamartoma
Diagnosing Genetic Epilepsy in a Resource-Constrained Setting – the South African experience
The genetic architecture of the pediatric epilepsies