Assessment of genetic variant burden in epilepsy-associated brain lesions

Item Type:	Article
Title:	Assessment of genetic variant burden in epilepsy-associated brain lesions
Creators Name:	Niestroj, L.M. and May, P. and Artomov, M. and Kobow, K. and Coras, R. and Pérez-Palma, E. and Altmüller, J. and Thiele, H. and Nürnberg, P. and Leu, C. and Palotie, A. and Daly, M.J. and Klein, K.M. and Beschorner, R. and Weber, Y.G. and Blümcke, I. and Lal, D.
Abstract:	It is challenging to estimate genetic variant burden across different subtypes of epilepsy. Herein, we used a comparative approach to assess the genetic variant burden and genotype-phenotype correlations in four most common brain lesions in patients with drug-resistant focal epilepsy. Targeted sequencing analysis was performed for a panel of 161 genes with a mean coverage of >400×. Lesional tissue was histopathologically reviewed and dissected from hippocampal sclerosis (n = 15), ganglioglioma (n = 16), dysembryoplastic neuroepithelial tumors (n = 8), and focal cortical dysplasia type II (n = 15). Peripheral blood (n = 12) or surgical tissue samples histopathologically classified as lesion-free (n = 42) were available for comparison. Variants were classified as pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics guidelines. Overall, we identified pathogenic and likely pathogenic variants in 25.9% of patients with a mean coverage of 383×. The highest number of pathogenic/likely pathogenic variants was observed in patients with ganglioglioma (43.75%; all somatic) and dysembryoplastic neuroepithelial tumors (37.5%; all somatic), and in 20% of cases with focal cortical dysplasia type II (13.33% somatic, 6.67% germline). Pathogenic/likely pathogenic positive genes were disorder specific and BRAF V600E the only recurrent pathogenic variant. This study represents a reference for the genetic variant burden across the four most common lesion entities in patients with drug-resistant focal epilepsy. The observed large variability in variant burden by epileptic lesion type calls for whole exome sequencing of histopathologically well-characterized tissue in a diagnostic setting and in research to discover novel disease-associated genes.
Keywords:	Brain, Brain Neoplasms, Drug Resistant Epilepsy, Epilepsy, Exome Sequencing, Ganglioglioma, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Germany, Glioma, Group I Malformations of Cortical Development, Sclerosis
Source:	European Journal of Human Genetics
ISSN:	1018-4813
Publisher:	Nature Publishing Group
Volume:	27
Number:	11
Page Range:	1738-1744
Date:	November 2019
Official Publication:	https://doi.org/10.1038/s41431-019-0484-4
PubMed:	View item in PubMed

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