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Comprehensive genomic biomarker discovery in patients with common and rare epileptic brain lesions

Subject Area Molecular and Cellular Neurology and Neuropathology
Human Genetics
Molecular Biology and Physiology of Neurons and Glial Cells
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 418080568
 
Final Report Year 2024

Final Report Abstract

Our interdisciplinary project team from Cologne, Erlangen, and Cleveland has carried out extensive genetic studies on neurosurgically resected brain tissue in 1073 patients with focal, drug-resistant epilepsy. For this purpose, we used either frozen (n=474) or formalin-fixed and paraffin-embedded (FFPE) tissue samples (n=599) from each patient. Each sample was microscopically examined to classify the lesion and isolate DNA from tissue sections. All objectives specified in the application have been successfully processed and published in six scientific papers so far (incl. 1x in revision). In addition, we are in the process of finalizing Bosselmann et al. / 3rd project objective. Key findings were as follows: 1 We were able to expand the landscape of somatic variants by 474 deep exome-wide sequencing (>350x) (1. project goal). PTPN11 was identified as a novel pathogen. Genotype-phenotype analyses revealed a positive correlation between the number of somatic variants and affected cells in the tissue with age at seizure onset and surgery. In 22% of cases, there was a change in histopathological classification. 2 Based on the aforementioned findings, we developed a new epilepsy panel of 122 candidate genes (2. project goal). This panel was examined in an extended cohort of 1386 samples. With this study, we can provide the first statistical evidence for the association of eight genes with lesional epilepsy and identify DYRK1A and EGF as additional pathogens in focal epilepsies. 3 We specifically looked at clinical correlates and biomarkers of genetically defined lesions in two patient cohorts (4. project goal). In all patients with somatic mutations in the SLC35A gene, we were able to histopathologically diagnose MOGHE (mild malformation with oligodendroglial hyperplasia). 64% of affected patients were seizure-free after surgery. In non-seizure-free patients with SLC35A2 mutations, successful galactose substitution was performed for the first time. This represents a milestone for personalized medicine in epileptology. 4 For the PTPN11 gene, we have seen an association with atypical gangliogliomas. Only 38% of affected patients became seizure-free after surgery. 5 We established a genotype-phenotype correlation for focal cortical dysplasia (FCD) type IIa with the DEPDC5 gene and for FCD type IIb with the MTOR gene (Honke et al., Acta Neuropathol Comm 2023). Postoperative seizure freedom was significantly worse in patients with FCDIIa. 6 The evaluation of the world's largest series of 24 epilepsy lesions using deep genome-wide sequencing is in progress and is being prepared for publication (3. project objective). In summary, our multidisciplinary team was able to redefine the map of genetic variants in lesional epilepsies and identify new phenotype-genotype correlations. This work now provides us with a genetically sound basis for a better understanding of focal epilepsies and their treatment options, such as galactose substitution in the presence of detectable SLC35A2 mutation.

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