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Title: Somatic Mosaic Mutation Gradient Detected in Trace Brain Tissue From Stereo-EEG Depth Electrodes.
Austin Authors: Ye, Zimeng;Bennett, Mark F ;Neal, Andrew;Laing, Joshua A;Hunn, Martin K;Wittayacharoenpong, Thanomporn;Todaro, Marian;Patel, Sheila K ;Bahlo, Melanie;Kwan, Patrick;O'Brien, Terence J;Scheffer, Ingrid E ;Berkovic, Samuel F ;Perucca, Piero ;Hildebrand, Michael S 
Affiliation: Neurology
Department of Neurosurgery, The Alfred Hospital, Melbourne, Australia
Medicine (University of Melbourne)
The Florey Institute of Neuroscience and Mental Health
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Australia
Murdoch Children's Research Institute, Parkville, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia
Department of Neurology, Royal Melbourne Hospital, Parkville, Australia
Department of Neurology, Alfred Hospital, Melbourne, Australia
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
Department of Neurosciences, The Central Clinical School, Monash University, Melbourne, Australia
Department of Neurology, St Vincent's Hospital, Fitzroy, Australia
Issue Date: 3-Oct-2022
Date: 2022
Publication information: Neurology 2022
Abstract: Mosaic pathogenic variants restricted to 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 stereo-electroencephalography (SEEG) electrodes. We studied a patient with non-lesional multifocal epilepsy undergoing pre-surgical evaluation with SEEG. Following explantation, 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 and DNA whole genome amplified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. Brain-specific GFAP protein assay enabled cell-of-origin analysis. We demonstrated a mosaic gradient for a novel pathogenic KCNT1 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 as the highest mutant allele fraction was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. Elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. This study demonstrates proof-of-concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.
DOI: 10.1212/WNL.0000000000201469
Journal: Neurology
PubMed URL: 36192176
Type: Journal Article
Appears in Collections:Journal articles

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