Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia.

Abstract

OBJECTIVES:

Focal cortical dysplasia (FCD) is a major cause of drug-resistant focal epilepsy in children, and the clinicopathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation-based classification of human brain tumors we examined whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtypes.

METHODS:

DNA methylomes and transcriptomes were generated from massive parallel sequencing in 15 surgical FCD specimens, matched with 5 epilepsy and 6 nonepilepsy controls.

RESULTS:

Differential hierarchical cluster analysis of DNA methylation distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNA methylation or gene expression was observed in mechanistic target of rapamycin (mTOR) pathway-related genes.

SIGNIFICANCE:

Our studies extend the evidence for disease-specific methylation signatures toward focal epilepsies in favor of an integrated clinicopathologic and molecular classification system of FCD subtypes incorporating genomic methylation.

• Authors: Katja Kobow, Mark Ziemann, Harikrishnan Kaipananickal, Ishant Khurana, Angelika Mühlebner, Martha Feucht, Johannes A Hainfellner, Thomas Czech, Eleonora Aronica, Tom Pieper, Hans Holthausen, Manfred Kudernatsch, Hajo Hamer, Burkhard S Kasper, Karl Rössler, Valerio Conti, Renzo Guerrini, Roland Coras, Ingmar Blümcke, Assam El-Osta, Antony Kaspi
• Journal: Epilepsia (Epilepsia) Vol. 60 Issue 6 Pg. 1091-1103 (Jun 2019) ISSN: 1528-1167 [Electronic] United States
• PMID: 31074842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

Chemical References

• RNA, Messenger
• DNA
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• Cluster Analysis
• DNA (genetics)
• DNA Methylation (genetics)
• Epilepsies, Partial (classification, genetics)
• Female
• Gene Expression Profiling
• Genome, Human
• Humans
• Infant
• Male
• Malformations of Cortical Development (classification, diagnostic imaging, genetics)
• Middle Aged
• RNA, Messenger (genetics)
• TOR Serine-Threonine Kinases (genetics)
• Tissue Banks
• Tomography, Emission-Computed, Single-Photon
• Tomography, X-Ray Computed
• Transcriptome
• Young Adult