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Eur J Hum Genet. 2019 Jul 29. doi: 10.1038/s41431-019-0484-4. [Epub ahead of print]

Assessment of genetic variant burden in epilepsy-associated brain lesions.

Author information

1
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
2
Luxembourg Centre for Systems Biomedicine, University Luxembourg, Luxembourg, Luxembourg.
3
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
4
Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
5
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
6
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
7
Institute of Neurology, University College London, London, UK.
8
Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
9
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
10
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
11
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
12
Epilepsy Center Frankfurt Rhine-Main, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
13
Department of Neuropathology, University of Tübingen, Tübingen, Germany.
14
Hertie Institute for Clinical Brain Research, Tübingen, Germany.
15
Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany. ingmar.bluemcke@uk-erlangen.de.
16
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. lald@ccf.org.
17
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. lald@ccf.org.
18
Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA. lald@ccf.org.
19
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. lald@ccf.org.
20
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. lald@ccf.org.

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.

PMID:
31358956
DOI:
10.1038/s41431-019-0484-4

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