Assessing the role of rare genetic variants in drug‐resistant, non‐lesional focal epilepsy

Wolking, Stefan; Moreau, Claudia; McCormack, Mark; Krause, Roland; Krenn, Martin; Berkovic, Samuel F.; Cavalleri, Gianpiero L.; Delanty, Norman; Depondt, Chantal; Johnson, Michael R.; Koeleman, Bobby P. C.; Kunz, Wolfram S.; Lerche, Holger; Marson, Anthony G; O’Brien, Terence J.; Petrovski, Steve; Sander, Josemir W.; Sills, Graeme J.; Striano, Pasquale; Zara, Federico; Zimprich, Fritz; Sisodiya, Sanjay M.; Girard, Simon; Cossette, Patrick

doi:10.1002/acn3.51374

Cited by 20 publications

(15 citation statements)

References 44 publications

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“…Interestingly, the presented cases revealed a severity gradient in phenotype with children (i.e., the probands) being more severely affected than their parents including drugresistant epilepsy and developmental delay, and they failed to achieve seizure freedom postsurgically [23]. These data confirm the hitherto overwhelming scientific interest and importance to understand the pathogenic action of DEPDC5 in human focal epilepsy [24][25][26][27]. Indeed, recent experimental research provided evidence for the functional consequences of complete loss of DEPDC5, i.e.…”

Section: Etiology and Genetics Matter In Focal Cortical Dysplasiasupporting

confidence: 61%

Neuropathology and epilepsy surgery

Hoffmann

Blümcke

2022

Current Opinion in Neurology

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Purpose of reviewNeurosurgical treatment of patients suffering from drug-resistant focal epilepsy is recognized as a successful, yet underutilized medical treatment option. By searching PubMed for articles published between January 2020 and September 2021 with the broad search terms 'neuropathology' AND 'epilepsy surgery', this review highlights the active field of etiology-based epilepsy research in human tissue. Recent findingsAll papers addressing the most common epileptogenic human brain disease entities, i.e. focal cortical dysplasia (FCD), brain tumors or hippocampal sclerosis, and written in English language were eligible for our review. We can conclude from this review that etiology-based studies are of foremost interest for (1) the development of prediction models for postsurgical seizure outcome; (2) decipher genetic and molecular alterations to better define disease entities and underlying molecular pathomechanisms, and (3) the translation of human tissue-derived biomarker into clinically useful diagnostics or novel therapeutic targets in the near future.

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Section: Etiology and Genetics Matter In Focal Cortical Dysplasiasupporting

confidence: 61%

Neuropathology and epilepsy surgery

Hoffmann

Blümcke

2022

Current Opinion in Neurology

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“…Whole-genome sequencing technology, genome-wide association studies, and polygenic risk score (PRS) open a broader window to understand the mechanisms of drug resistance and specific ASM responses. Several candidate rare genetic variants were found in the exome-based research of patients with non-familial non-acquired focal epilepsy and DEPDC5 was regarded as a potential risk factor for drug resistance ( 31 ). For the specific drug response, common genetic variants were not significantly associated with common ASMs in a study containing 3,649 individuals with focal epilepsy or generalized genetic epilepsy ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Current trends and hotspots in drug-resistant epilepsy research: Insights from a bibliometric analysis

Zhong

Liu

et al. 2022

Front. Neurol.

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BackgroundDrug-resistance is a significant clinical issue in persons with epilepsy. In the past few years, many studies have been published investigating the management of drug-resistant epilepsy (DRE); however, no systematic and quantitative evaluation of this research has been performed. Therefore, a bibliometric analysis was conducted to demonstrate the current status of DRE research and to reflect the trends and hotspots within the field.MethodsWe retrieved publications on DRE published between 2011 and 2021 from the Science Citation Index Expanded of the Web of Science Core Collection. All articles related to DRE were included in this study. VOSviewer, R software, and CiteSpace were used to perform bibliometric research.ResultsA total of 3,088 original articles were included in this study. The number of publications on DRE has continued to increase over the past 11 years. The USA published the most papers with the highest number of citations and H-index. The National Institutes of Health and the University of Toronto were the most prolific funding agency and affiliation, respectively. Epilepsy & Behavior and Epilepsia ranked first as the most prolific and co-cited journals, respectively. The keywords “cannabidiol”, “neuromodulation”, “seeg” and “perampanel” revealed recent research hotspots. The top 100 most cited papers were classified into eight main topics, of which pharmacotherapy, disease mechanisms/pathophysiology, and neuromodulation were the three most important topics.ConclusionsThis analysis of bibliometric data demonstrated that DRE has always been a topical area of research. The mechanisms of epilepsy and therapies have been the focus of DRE research, and innovative antiseizure medications and surgical approaches are fast-developing research trends.

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“…28 and in Wolking et al . 36 respectively. CNVs on WGS and WES were called using two software, CNVkit 37 and Control-FREEC 38 .…”

Section: Methodsmentioning

confidence: 98%

“…Duplications and deletions were considered separately. Detailed sequencing methods for WGS and WES are described in Moreau et al 28 and in Wolking et al 36 respectively. CNVs on WGS and WES were called using two software, CNVkit 37 and Control-FREEC 38 .…”

Section: Cnv Validationmentioning

confidence: 99%

Assessment of burden and segregation profiles of CNVs in patients with epilepsy

Moreau

Tremblay

Wolking

et al. 2022

Preprint

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Objective: Microdeletions are associated with different forms of epilepsy but show incomplete penetrance, which is not well understood. We aimed to assess whether unmasked variants or double CNVs could explain incomplete penetrance. Methods: We analyzed copy number variants (CNVs) in 603 patients with four different subgroups of epilepsy and 945 controls. CNVs were called from genotypes and validated on whole genome (WGS) or exome sequences (WES). CNV burden difference between patients and controls was obtained by fitting a logistic regression. CNV burden was assessed for small and large (> 1Mb) deletions and duplications and for deletions overlapping different genes set. Results: Large deletions were enriched in genetic generalized epilepsies (GGE) compared to controls. We also found an enrichment of deletions in epilepsy genes and hotspots for GGE. We did not find truncating or functional variants that could have been unmasked by the deletions. We observed a double CNV hit in two patients. One patient also carried a de novo deletion in the 22q11.2 hotspot. Interpretation: We could corroborate previous findings of an enrichment of large microdeletions and deletions in epilepsy genes in GGE. We could also replicate that microdeletions show incomplete penetrance. However, we could not validate the hypothesis of unmasked variants nor the hypothesis of double CNVs to explain the incomplete penetrance. We found a de novo hit on 22q11.2 that could be of interest. We also observed GGE families carrying a deletion on 15q13.3 hotspot that could be investigated in the Quebec founder population.

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Assessing the role of rare genetic variants in drug‐resistant, non‐lesional focal epilepsy

Cited by 20 publications

References 44 publications

Neuropathology and epilepsy surgery

Neuropathology and epilepsy surgery

Current trends and hotspots in drug-resistant epilepsy research: Insights from a bibliometric analysis

Assessment of burden and segregation profiles of CNVs in patients with epilepsy

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