{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:03:32Z","timestamp":1790219012632,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R00NS089858"],"award-info":[{"award-number":["R00NS089858"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NUCATS","award":["TR001423"],"award-info":[{"award-number":["TR001423"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,6,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions, but these variants are increasingly detected and reported by clinical genetic testing in individuals with epilepsy. To exemplify this latter point, here we describe a cohort of 12 individuals with biallelic SZT2 variants and phenotypic overlap with SZT2-related neurodevelopmental disorders. However, the majority of individuals carried one or more SZT2 variants of uncertain significance (VUS), highlighting the need for functional characterization to determine, which, if any, of these VUS were pathogenic. Thus, we developed a novel individualized platform to identify SZT2 loss-of-function variants in the context of mTORC1 signalling and reclassify VUS. Using this platform, we identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis revealed that this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Moreover, this approach allowed us to tentatively reclassify all of the VUS in our cohort of 12 individuals, identifying five individuals with biallelic pathogenic or likely pathogenic variants. Clinical features of these five individuals consisted of early-onset seizures (median 24 months), focal seizures, developmental delay and macrocephaly similar to previous reports. However, we also show a widening of the phenotypic spectrum, as none of the five individuals had corpus callosum abnormalities, in contrast to previous reports. Overall, we present a rapid assay to resolve VUS in SZT2, identify a founder variant in individuals of Ashkenazi Jewish ancestry, and demonstrate that corpus callosum abnormalities is not a hallmark feature of this condition. Our approach is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1\/2, MTOR and NPRL2\/3.<\/jats:p>","DOI":"10.1093\/brain\/awab451","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T15:12:31Z","timestamp":1639667551000},"page":"1939-1948","source":"Crossref","is-referenced-by-count":12,"title":["mTORC1 functional assay reveals\n                    <i>SZT2<\/i>\n                    loss-of-function variants and a founder in-frame deletion"],"prefix":"10.1093","volume":"145","author":[{"given":"Jeffrey D","family":"Calhoun","sequence":"first","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam C","family":"Aziz","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah C","family":"Happ","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Gunti","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen","family":"Gleason","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najma","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Zeng","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Hiller","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Bryant","sequence":"additional","affiliation":[{"name":"Ann and Robert H. Lurie Children\u2019s Hospital of Chicago Epilepsy Center and Division of Neurology , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divakar S","family":"Mithal","sequence":"additional","affiliation":[{"name":"Ann and Robert H. Lurie Children\u2019s Hospital of Chicago Epilepsy Center and Division of Neurology , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Bellinski","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Kinsley","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Grimmel","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University of T\u00fcbingen , T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva M C","family":"Schwaibold","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Heidelberg University , Heidelberg 69120 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance","family":"Smith-Hicks","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Kennedy Krieger Institute , Baltimore, MD 21205 , USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chassevent","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Kennedy Krieger Institute , Baltimore, MD 21205 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Scala","sequence":"additional","affiliation":[{"name":"Giannina Gaslini Children\u2019s Hospital , Genova, GE 16147 , Italy"},{"name":"Medical Genetic Unit, IRCCS Istituto G.Gaslini , 16147 Genoa , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Accogli","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Specialized Medicine, Montreal Children's Hospital, McGill University Health Centre (MUHC) , Montreal, QC, H4A 3J1 , Canada"},{"name":"Department of Human Genetics, McGill University , Montreal, QC , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalaura","family":"Torella","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Specialized Medicine, Montreal Children's Hospital, McGill University Health Centre (MUHC) , Montreal, QC, H4A 3J1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Giannina Gaslini Children\u2019s Hospital , Genova, GE 16147 , Italy"},{"name":"Medical Genetic Unit, IRCCS Istituto G.Gaslini , 16147 Genoa , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Capra","sequence":"additional","affiliation":[{"name":"Giannina Gaslini Children\u2019s Hospital , Genova, GE 16147 , Italy"},{"name":"Medical Genetic Unit, IRCCS Istituto G.Gaslini , 16147 Genoa , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne M","family":"Bird","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University , Montreal, QC , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9333-4162","authenticated-orcid":false,"given":"Issam","family":"Ben-Sahra","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM) , Pozzuoli, NA 80078 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Ekhilevich","sequence":"additional","affiliation":[{"name":"San Diego Department of Pediatrics and Rady Children\u2019s Hospital Division of Dysmorphology\/Genetics, University of California , San Diego, CA 92161 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tova","family":"Hershkovitz","sequence":"additional","affiliation":[{"name":"San Diego Department of Pediatrics and Rady Children\u2019s Hospital Division of Dysmorphology\/Genetics, University of California , San Diego, CA 92161 , USA"},{"name":"Department of Biochemistry and Molecular Genetics, Northwestern Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Weiss","sequence":"additional","affiliation":[{"name":"San Diego Department of Pediatrics and Rady Children\u2019s Hospital Division of Dysmorphology\/Genetics, University of California , San Diego, CA 92161 , USA"},{"name":"Department of Biochemistry and Molecular Genetics, Northwestern Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Millichap","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"},{"name":"Ann and Robert H. Lurie Children\u2019s Hospital of Chicago Epilepsy Center and Division of Neurology , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth E","family":"Gerard","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4945-3628","authenticated-orcid":false,"given":"Gemma L","family":"Carvill","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL 60610 , USA"},{"name":"Genetics Institute, Rambam Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa , Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa 3200003 , Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,3]]},"reference":[{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1111\/j.1601-183X.2009.00509.x","article-title":"Szt2, a novel gene for seizure threshold in mice","volume":"8","author":"Frankel","year":"2009","journal-title":"Genes Brain Behav"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ajhg.2013.07.005","article-title":"Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum","volume":"93","author":"Basel-Vanagaite","year":"2013","journal-title":"Am J Hum Genet"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"e82810","DOI":"10.1371\/journal.pone.0082810","article-title":"An amino acid deletion in SZT2 in a family with non-syndromic intellectual 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callosum","volume":"40","author":"Nakamura","year":"2018","journal-title":"Brain Dev"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1002\/ajmg.a.38717","article-title":"Mutations in SZT2 result in early-onset epileptic encephalopathy and leukoencephalopathy","volume":"176","author":"Pizzino","year":"2018","journal-title":"Am J Med Genet A"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1007\/s13258-018-0673-5","article-title":"A novel homozygous mutation in SZT2 gene in Saudi family with developmental delay, macrocephaly and epilepsy","volume":"40","author":"Naseer","year":"2018","journal-title":"Genes Genomics"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"103556","DOI":"10.1016\/j.ejmg.2018.10.008","article-title":"SZT2 mutation in a boy with intellectual disability, seizures and autistic features","volume":"62","author":"Kariminejad","year":"2019","journal-title":"Eur J Med Genet"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"245","DOI":"10.5582\/irdr.2018.01117","article-title":"Identification of a rare homozygous SZT2 variant due to uniparental disomy in a patient with a neurodevelopmental disorder","volume":"7","author":"Imaizumi","year":"2018","journal-title":"Intractable Rare Dis Res"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.1002\/ccr3.1868","article-title":"Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early-onset of epileptic encephalopathy","volume":"6","author":"Uittenbogaard","year":"2018","journal-title":"Clin Case Rep"},{"key":"2023033018214862600_","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.seizure.2018.12.021","article-title":"Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and 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