{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:49:34Z","timestamp":1793141374751,"version":"4.5.0"},"reference-count":68,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["Investigator Program"],"award-info":[{"award-number":["Investigator Program"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS032457"],"award-info":[{"award-number":["R01NS032457"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG070921"],"award-info":[{"award-number":["R01AG070921"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K08NS128272"],"award-info":[{"award-number":["K08NS128272"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:p>While it is widely accepted that somatic variants that activate the PI3K-mTOR pathway are a major cause of drug-resistant focal epilepsy, typically associated with focal cortical dysplasia (FCD) type 2, understanding the mechanism of epileptogenesis requires identifying genotype-associated changes at the single-cell level, which is technically challenging with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 18 FCD type 2 samples removed surgically for treatment of drug-resistant epilepsy, and 17 non-FCD control samples, and analyzed additional published data comprising &gt;400,000 single nuclei. We also performed simultaneous single-nucleus genotyping and gene expression analysis using two independent approaches: 1) a method that we called genotyping of transcriptomes enhanced with nanopore sequencing (GO-TEN) that combines targeted cDNA long-read sequencing with snRNA-seq, 2) ResolveOME snRNA-seq and DNA genotyping. snRNA-seq showed similar cell identities and proportions between cases and controls, suggesting that mosaic pathogenic variants in PI3K-mTOR pathway genes in FCD exert their effect by disrupting transcription in conserved cell types. GO-TEN and ResolveOME analyses confirmed that pathogenic variant-carrying cells have well-differentiated neuronal or glial identities, with enrichment of variants in cells of the neuroectodermal lineage, pointing to cortical neural progenitors as possible loci of somatic mutation. Within FCD type 2 lesions, we identified upregulation of PI3K-mTOR signaling and related pathways in variant-carrying neurons, downregulation of these pathways in non-variant-carrying neurons, as well as associated changes in microglial activation, cellular metabolism, synaptic homeostasis, and neuronal connectivity, all potentially contributing to epileptogenesis. These genotype-specific changes in mosaic lesions highlight potential disease mechanisms and therapeutic targets.<\/jats:p>","DOI":"10.1073\/pnas.2509622122","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T17:51:53Z","timestamp":1752774713000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs"],"prefix":"10.1073","volume":"122","author":[{"given":"Sara","family":"Bizzotto","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research","place":["Boston"]},{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston"]},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]},{"name":"Imagine Institute, Team Somatic Mosaicism in Neurodevelopment and Disease, Universit\u00e9 Paris Cit\u00e9","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5997-5633","authenticated-orcid":false,"given":"Maya","family":"Talukdar","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research","place":["Boston"]},{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston"]},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]},{"name":"Harvard\/Massachusetts Institute of Technology MD-PhD Program, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward A.","family":"Stronge","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, 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Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]},{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0416-2854","authenticated-orcid":false,"given":"August Yue","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research","place":["Boston"]},{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston"]},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwen","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical 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Hospital, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Boston Children\u2019s Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne","place":["Heidelberg, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Reutens","sequence":"additional","affiliation":[{"name":"Centre for Advanced Imaging, The University of Queensland and Royal Brisbane and Women\u2019s Hospital","place":["Herston, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saul A.","family":"Mullen","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of 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R. Marks Unifying comprehensive genomics and transcriptomics in individual cells to illuminate oncogenic and drug resistance mechanisms. bioRxiv [Preprint] (2022). https:\/\/doi.org\/10.1101\/2022.04.29.489440 (Accessed 20 July 2023).","DOI":"10.1101\/2022.04.29.489440"},{"key":"e_1_3_4_11_2","unstructured":"S. Bizzotto Data from \u201cHuman Epilepsy Genetics: Mosaic Mutations in Focal Epilepsy.\u201d dbGaP. https:\/\/www.ncbi.nlm.nih.gov\/projects\/gap\/cgi-bin\/study.cgi?study_id=phs004124.v1.p1. Deposited 2 July 2025."},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.02.025"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","unstructured":"S. N. Kim Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex. bioRxiv [Preprint] (2023). https:\/\/doi.org\/10.1101\/2023.11.06.565899 (Accessed 7 November 2023).","DOI":"10.1101\/2023.11.06.565899"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.add7046"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01276-9"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0929"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408864102"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.11.005"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.09.010"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03465-8"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1506-7"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btac582"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2006.01.002"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-005-1062-0"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/oons\/kvad004"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.042007850.x"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-018-3994-3"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03363.x"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2024.106491"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-35892-5"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","unstructured":"G. Korotkevich Fast gene set enrichment analysis. bioRxiv [Preprint] (2021). https:\/\/doi.org\/10.1101\/060012 (Accessed 1 February 2021).","DOI":"10.1101\/060012"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.12.066"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106249"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2260-18.2019"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4351"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016163"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.002"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2022.12.005"},{"key":"e_1_3_4_43_2","first-page":"D845","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Pinero J.","year":"2020","unstructured":"J. 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