{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T03:24:24Z","timestamp":1781580264772,"version":"3.54.5"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T00:00:00Z","timestamp":1551052800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["13200"],"award-info":[{"award-number":["13200"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>We investigated the contribution to sporadic focal epilepsies (<jats:styled-content style=\"fixed-case\">FE<\/jats:styled-content>) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>)complex 1 (<jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We collected genetic data of 121 Italian isolated <jats:styled-content style=\"fixed-case\">FE<\/jats:styled-content> cases and 512 controls by Whole Exome Sequencing (<jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>) and single\u2010molecule Molecular Inversion Probes (sm<jats:styled-content style=\"fixed-case\">MIP<\/jats:styled-content>s) targeting 10 genes of the <jats:styled-content style=\"fixed-case\">GATOR<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">GATOR<\/jats:styled-content>2, and <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> complexes. We collapsed \u201cqualifying\u201d variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in <jats:styled-content style=\"fixed-case\">FE<\/jats:styled-content> patients (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.006; exact unconditional test, one\u2010tailed). Pathogenic variants were identified in <jats:italic><jats:styled-content style=\"fixed-case\">DEPDC<\/jats:styled-content>5<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>2,<\/jats:italic> both major genes for Mendelian <jats:styled-content style=\"fixed-case\">FE<\/jats:styled-content> syndromes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings support the contribution of ultrarare variants in genes in the <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> pathway complexes <jats:styled-content style=\"fixed-case\">GATOR<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> to the risk of sporadic <jats:styled-content style=\"fixed-case\">FE<\/jats:styled-content> and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.722","type":"journal-article","created":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T07:16:47Z","timestamp":1551165407000},"page":"475-485","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies"],"prefix":"10.1002","volume":"6","author":[{"given":"Tommaso","family":"Pippucci","sequence":"first","affiliation":[{"name":"Medical Genetics Unit Polyclinic Sant'Orsola\u2010Malpighi University Hospital Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Licchetta","sequence":"additional","affiliation":[{"name":"IRCCS 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