The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Somatic Mosaic Pathogenic Variant Gradient Detected in Trace Brain Tissue From Stereo-EEG Depth Electrodes
Abstract
BACKGROUND AND OBJECTIVES: Mosaic pathogenic variants restricted to the brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereoelectroencephalography (SEEG) electrodes. METHODS: We studied a patient with nonlesional multifocal epilepsy undergoing presurgical evaluation with SEEG. After explantation, the electrodes were divided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippocampus/temporal neocortex). Tissue from each pool was processed for trace DNA that was whole genome amplified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. A brain-specific glial fibrillary acidic protein (GFAP) assay enabled cell-of-origin analysis. RESULTS: loss-of-function variant (c.530G>A, p.W177X) predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings because the highest variant allele frequency was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. An elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. DISCUSSION: This study demonstrates a proof of concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.
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“Somatic mosaicism can be found in brain-derived DNA at low levels on surgical specimens, cerebrospinal fluid or implanted EEG electrodes 122, 177, 178 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [177]
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Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594
KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum
Bonardi, C. M., Heyne, H., Fiannacca, M., Fitzgerald, M. P., Gardella, E., Gunning, B. W., Olofsson, K., Lesca, G., Verbeek, N. E., Stamberger, H., et al. (2021) · Brain · doi:10.1093/brain/awab219 · Cited by 114
Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain
Ye, Z., Chatterton, Z., Pflueger, J., Damiano, J. A., McQuillan, L., Simon Harvey, A., Malone, S., Do, H., Maixner, W., Schneider, A., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcaa235 · Cited by 77
Self-citationEvely, K. M., Pryce, K. D., & Bhattacharjee, A. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.03.035 · Cited by 34
Montier, L., Haneef, Z., Gavvala, J. R., Yoshor, D., North, R. Y., Verla, T. G., Ness, P. C. V., Drabek, J. M., & Goldman, A. M. (2019) · Epilepsia · doi:10.1111/epi.16328 · Cited by 31
Ye, Z., Bennett, M. F., Bahlo, M., Scheffer, I. E., Berkovic, S. F., Perucca, P., & Hildebrand, M. S. (2021) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2021.1981288 · Cited by 9
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Developmental and epileptic encephalopathies
Scheffer, I. E., Zuberi, S., Mefford, H. C., Guerrini, R., & McTague, A. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00546-6 · Cited by 158
Self-citationmTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy
Gerasimenko, A., Baldassari, S., & Baulac, S. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106144 · Cited by 85
Khoshkhoo, S., Wang, Y., Chahine, Y., Erson-Omay, Z., Robert, S. M., Kiziltug, E., Damisah, E. C., Nelson-Williams, C. J., Zhu, G., Kong, W., et al. (2023) · JAMA Neurology · doi:10.1001/jamaneurol.2023.0473 · Cited by 83
Self-citationMan, A., Scipio, M. D., Grewal, S., Suk, Y., Trinari, E., Ejaz, R., & Whitney, R. (2024) · Genes · doi:10.3390/genes15030332 · Cited by 55
Brain somatic mosaicism in epilepsy: Bringing results back to the clinic
D’Gama, A. M., & Poduri, A. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106104 · Cited by 40
Metadata
- Authors
- Ye, Z., Bennett, M. F., Neal, A., Laing, J. A., Hunn, M. K., Wittayacharoenpong, T., Todaro, M., Patel, S. K., Bahlo, M., Kwan, P., O'Brien, T. J., Scheffer, I. E., Berkovic, S. F., Perucca, P., & Hildebrand, M. S.
- Affiliations
- The Royal Melbourne Hospital (AU)
- ORCID
- Venue
- Neurology
- Published
- 2022-12-06
- Volume
- 99
- Issue
- 23
- Pages
- 1036-1041
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W4300817072
- Cited by
- 35
- References
- 6
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 13
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- somatic mosaicism, pathogenic variants, focal epilepsy, stereoelectroencephalography, nonsense-mediated mRNA decay, glial fibrillary acidic protein, cell of origin, epileptogenic zone, preoperative assessment
- MeSH terms
- Potassium Channels, Sodium-Activated, Brain, DNA, Electrodes, Implanted, Electroencephalography, Epilepsies, Partial, Humans, Nerve Tissue Proteins, Stereotaxic Techniques
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