{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:17:48Z","timestamp":1792509468532,"version":"4.5.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Brotman-Baty Institute"},{"name":"Jordan\u2019s Guardian Angels and the Sunderland Foundation"},{"DOI":"10.13039\/501100009888","name":"Tuscany Region","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009888","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1R01NS092772"],"award-info":[{"award-number":["1R01NS092772"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data.<\/jats:p>\n                  <jats:p>Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.<\/jats:p>","DOI":"10.1093\/brain\/awab376","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:36:08Z","timestamp":1633480568000},"page":"925-938","source":"Crossref","is-referenced-by-count":56,"title":["Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care"],"prefix":"10.1093","volume":"145","author":[{"given":"Filomena","family":"Pirozzi","sequence":"first","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Berkseth","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rylee","family":"Shear","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine , Baltimore, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew E","family":"Timms","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Sulc","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Pao","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Oyama","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Forzano","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Guy's and St Thomas NHS Foundation Trust and King's College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Conti","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily S","family":"Doherty","sequence":"additional","affiliation":[{"name":"Section of Clinical Genetics, Carilion Clinic Children's Hospital , Roanoke, VA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulagna C","family":"Saitta","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California Los Angeles , Los Angeles, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M","family":"Lockwood","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington , Seattle, WA , USA"},{"name":"Brotman-Baty Institute for Precision Medicine , University of Minnesota, Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin C","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington , Seattle, WA , USA"},{"name":"Brotman-Baty Institute for Precision Medicine , University of Minnesota, Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7681-2844","authenticated-orcid":false,"given":"William B","family":"Dobyns","sequence":"additional","affiliation":[{"name":"Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota , Minneapolis, MN , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Novotny","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"},{"name":"Division of Pediatric Neurology, Department of Neurology, Seattle Children\u2019s Hospital , Seattle, WA , USA"},{"name":"Department of Neurology, University of Washington , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason N N","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Radiology, Seattle Children\u2019s Hospital , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell P","family":"Saneto","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute , Seattle, WA , USA"},{"name":"Division of Pediatric Neurology, Department of Neurology, Seattle Children\u2019s Hospital , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth","family":"Friedman","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research, Seattle Children\u2019s Hospital , Seattle, WA , 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WA , USA"},{"name":"Division of Genetic Medicine, Department of Pediatrics, University of Washington , Seattle, WA , USA"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,31]]},"reference":[{"issue":"11","key":"2022110305480682200_awab376-B1","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/s41582-020-0395-6","article-title":"International consensus recommendations on the diagnostic work-up for malformations of cortical development","volume":"16","author":"Oegema","year":"2020","journal-title":"Nat Rev Neurol."},{"issue":"7","key":"2022110305480682200_awab376-B2","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1001\/jamaneurol.2016.0363","article-title":"Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary 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