The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

Journal
Brain
ISSN
0006-8950
1460-2156
Date Issued
2022
Author(s)
Javier A López-Rivera
Costin Leu
Marie Macnee
Jean Khoury
Lucas Hoffmann
Roland Coras
Katja Kobow
Nisha Bhattarai
Hajo Hamer
Sebastian Brandner
Karl Rössler
Christian G Bien
Thilo Kalbhenn
Tom Pieper
Till Hartlieb
Elizabeth Butler
Giulio Genovese
Kerstin Becker
Janine Altmüller
Lisa-Marie Niestroj
Lisa Ferguson
Robyn M Busch
Peter Nürnberg
Imad Najm
Ingmar Blümcke
Dennis Lal
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85153124008
WoS ID
WOS:000917584200001
DOI
URL
URL Institutional Repository
Abstract
<jats:title>Abstract</jats:title>
<jats:p>Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (&gt;350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed ‘second hit’ disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.</jats:p>
Cite this document
López-Rivera, J. A., Leu, C., Macnee, M., Khoury, J., Hoffmann, L., Coras, R., Kobow, K., Bhattarai, N., Pérez-Palma, E., Hamer, H., Brandner, S., Rössler, K., Bien, C. G., Kalbhenn, T., Pieper, T., Hartlieb, T., Butler, E., Genovese, G., Becker, K., … Lal, D. (2023). The genomic landscape across 474 surgically accessible epileptogenic human brain lesions. Brain, 146(4), 1342-1356. https://doi.org/10.1093/brain/awac376
Subjects
epilepsy

; 

genetics

; 

hippocampal sclerosis

; 

low-grade epilepsy-associated tumour

; 

malformation of cortical development

; 

brain

; 

drug resistant epilepsy

; 

epilepsies, partial

; 

epilepsy

; 

genomics

; 

humans

; 

malformations of cortical development

; 

nucleotides

; 

dna

; 

hyalin

; 

protein tyrosine phosphatase shp 2

; 

nucleotide

; 

adult

; 

alexander disease

; 

article

; 

brain damage

; 

brain tissue

; 

chromosome 1

; 

chromosome 19

; 

chromosome 1q

; 

chromosome 20

; 

chromosome 22

; 

chromosome 5

; 

chromosome 7

; 

chromosome duplication

; 

cohort analysis

; 

conformational transition

; 

cortical dysplasia

; 

descriptive research

; 

epilepsy

; 

false discovery rate

; 

female

; 

genetic association

; 

genetic variability

; 

genomics

; 

genotype phenotype correlation

; 

glioma

; 

heterotopia

; 

hippocampal sclerosis

; 

histopathology

; 

human

; 

human tissue

; 

major clinical study

; 

male

; 

microgyria

; 

noonan syndrome

; 

onset age

; 

refractory epilepsy

; 

sensitivity and specificity

; 

single nucleotide polymorphism

; 

whole exome sequencing

; 

brain

; 

complication

; 

cortical dysplasia

; 

epilepsy

; 

focal epilepsy

; 

genetics

; 

genomics

; 

metabolism

; 

pathology

; 

refractory epilepsy