{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:47:45Z","timestamp":1783702065277,"version":"3.55.0"},"reference-count":35,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      The\n                      <jats:italic>FBXW7<\/jats:italic>\n                      gene encodes a substrate\u2010recognition component of the Skp1\u2010Cul1\u2010F\u2010box (SCF) E3 ubiquitin ligase complex, which targets key regulatory proteins for proteasomal degradation. Recently, loss\u2010of\u2010function\n                      <jats:italic>FBXW7<\/jats:italic>\n                      variants have been associated with a novel neurodevelopmental disorder characterized by heterogeneous clinical features. Most reported pathogenic variants cluster within the WD40 domains, while variants in other regions, such as the F\u2010box domain, remain poorly characterized. In this study, we performed trio\u2010exome sequencing on a 3\u2010year\u2010old girl with Early\u2010Onset Childhood Absence Epilepsy. We analyzed the identified\n                      <jats:italic>FBXW7<\/jats:italic>\n                      variant using multiple in silico tools for pathogenicity prediction and structural modeling. Clinical phenotype was compared with previously reported cases. We identified a novel de novo missense variant in\n                      <jats:italic>FBXW7<\/jats:italic>\n                      , c.926G&gt;C; p.(Arg309Pro), affecting a highly conserved residue in the F\u2010box domain. Notably, unlike prior cases predominantly associated with WD40 domain variants and severe phenotypes, our patient exhibited a much milder clinical presentation consisting of isolated, drug\u2010responsive absence seizures without intellectual disability. Structural modeling predicted significant impairment in protein\u2013protein binding affinity, particularly with the SCF complex component SKP1, supporting a potentially disruptive effect of the p.(Arg309Pro) substitution on complex assembly. Overall, our findings expand the genotypic and phenotypic spectrum of FBXW7\u2010related disorders. Variants in the F\u2010box domain may result in milder neurological phenotypes compared to those in the WD40 domains, suggesting domain\u2010specific effects and potentially distinct pathogenic mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain Language Summary<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>FBXW7<\/jats:italic>\n                      gene helps regulate the stability of many proteins essential for brain development and function. Changes in this gene have recently been linked to neurodevelopmental disorders with epilepsy. We identified a new\n                      <jats:italic>FBXW7<\/jats:italic>\n                      variant in a 3\u2010year\u2010old girl with early\u2010onset absence epilepsy. Computer\u2010based modeling suggests that this change weakens the protein's normal interactions. Our findings broaden the spectrum of\n                      <jats:italic>FBXW7<\/jats:italic>\n                      \u2010related disorders and indicate that variants in different gene regions may result in variable clinical severity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi4.70227","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T09:51:51Z","timestamp":1770976311000},"page":"643-651","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Isolated absence epilepsy associated with a de novo\n                    <i>FBXW7<\/i>\n                    missense variant in the F\u2010box domain"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2323-4382","authenticated-orcid":false,"given":"Anees","family":"Muhammad","sequence":"first","affiliation":[{"name":"Institute of Basic Medical Sciences Khyber Medical University  Peshawar Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-0601","authenticated-orcid":false,"given":"Mohammad Sadegh Shams","family":"Nosrati","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Istituto Giannina Gaslini  Genoa Italy"},{"name":"Department of Neurosciences, Rehabilitation Ophthalmology, Genetics, Maternal and Child Health, University of Genoa  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-2056","authenticated-orcid":false,"given":"Alireza","family":"Dostmohammadi","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biophysics Faculty of Biology and Centre for Medical Biotechnology (ZMB), University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-1322","authenticated-orcid":false,"given":"Francesca","family":"Madia","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Istituto Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5122-4029","authenticated-orcid":false,"given":"Maria Margherita","family":"Mancardi","sequence":"additional","affiliation":[{"name":"Unit of Child Neuropsychiatry, EpiCARE Network, IRCCS Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Fornarino","sequence":"additional","affiliation":[{"name":"S.C. Child and Adolescent Neuropsychiatry, ASL2 Liguria  Savona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5375-5197","authenticated-orcid":false,"given":"Luca","family":"Bosisio","sequence":"additional","affiliation":[{"name":"Unit of Child Neuropsychiatry, EpiCARE Network, IRCCS Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2432-2114","authenticated-orcid":false,"given":"Zahra Hoseini","family":"Tavassol","sequence":"additional","affiliation":[{"name":"Obesity and Eating Habits Research Center, Endocrinology and Metabolism Clinical Sciences Institute Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-9717","authenticated-orcid":false,"given":"Mir Davood","family":"Omrani","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine Shahid Beheshti University of Medical Sciences  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9744-5222","authenticated-orcid":false,"given":"Federico","family":"Zara","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Istituto Giannina Gaslini  Genoa Italy"},{"name":"Department of Neurosciences, Rehabilitation Ophthalmology, Genetics, Maternal and Child Health, University of Genoa  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2194-7239","authenticated-orcid":false,"given":"Marcello","family":"Scala","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Istituto Giannina Gaslini  Genoa Italy"},{"name":"Department of Neurosciences, Rehabilitation Ophthalmology, Genetics, Maternal and Child Health, University of Genoa  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24002"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10123395"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2020.1713101"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.02.001"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201034264\u2010y"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2011.03.017"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2024.03.014"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12007"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468\u20101331.2012.03871.x"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18655"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.03.002"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2024.1436462"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010023\u201001513\u20107"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.736008"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24015"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38593"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102308\u20107"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab266"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2314853121"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad472"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks539"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410\u2010248"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad989"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.3"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae412"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz383"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038\u2010024\u201001255\u20104"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010018\u20100292\u20102"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.07.003"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy406"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2025.101206"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2022.09.006"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/416703a"}],"container-title":["Epilepsia 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