{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:22:43Z","timestamp":1790760163082,"version":"4.1.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018726","name":"Epilepsy Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018726","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006662","name":"National Institute on Handicapped Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006662","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["31003A_182632"],"award-info":[{"award-number":["31003A_182632"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lejeune Foundation","award":["#1838-2019A"],"award-info":[{"award-number":["#1838-2019A"]}]},{"name":"Blackswan Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.<\/jats:p>","DOI":"10.1093\/hmg\/ddac225","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T16:19:25Z","timestamp":1662481165000},"page":"580-594","source":"Crossref","is-referenced-by-count":16,"title":["Germline homozygous missense <i>DEPDC5<\/i> variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8393-4444","authenticated-orcid":false,"given":"Athina","family":"Ververi","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK"},{"name":"Genetic Unit, 1st Obstetrics-Gynaecology Department, Aristotle University of Thessaloniki, Papageorgiou General Hospital , Thessaloniki , Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Zagaglia","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology , London , UK"},{"name":"Chalfont Centre for Epilepsy , Chalfont St. Peter , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Menzies","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0915-5028","authenticated-orcid":false,"given":"Julia","family":"Baptista","sequence":"additional","affiliation":[{"name":"Faculty of Health, University of Plymouth , Plymouth , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0713-4602","authenticated-orcid":false,"given":"Richard","family":"Caswell","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust , Exeter , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Baulac","sequence":"additional","affiliation":[{"name":"Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Sorbonne Universit\u00e9 , F-75013 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Ellard","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust , Exeter , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Lynch","sequence":"additional","affiliation":[{"name":"Academic Centre on Rare Diseases, University College Dublin School of Medicine and Medical Science , Dublin , Ireland"},{"name":"Department of Clinical Genetics, Children's Health Ireland (CHI) at Crumlin , Dublin , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Genomics England Research Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S","family":"Jacques","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health , London , UK"},{"name":"Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maninder Singh","family":"Chawla","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Oslo University Hospital , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Heier","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience for Children, Oslo University Hospital , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari Ann","family":"Kulseth","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger-Lise","family":"Mero","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Katrine","family":"V\u00e5tevik","sequence":"additional","affiliation":[{"name":"National Center for Epilepsy-SSE, Oslo Univeristy Hospital , Oslo , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichraf","family":"Kraoua","sequence":"additional","affiliation":[{"name":"Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of Medicine of Tunis, University of Tunis El Manar , Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanene","family":"Ben Rhouma","sequence":"additional","affiliation":[{"name":"Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of Medicine of Tunis, University of Tunis El Manar , Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thouraya","family":"Ben Younes","sequence":"additional","affiliation":[{"name":"Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of Medicine of Tunis, University of Tunis El Manar , Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zouhour","family":"Miladi","sequence":"additional","affiliation":[{"name":"Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of Medicine of Tunis, University of Tunis El Manar , Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilhem","family":"Ben Youssef Turki","sequence":"additional","affiliation":[{"name":"Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of Medicine of Tunis, University of Tunis El Manar , Tunis , Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy D","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Clement","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Eltze","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust , London , 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UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marios","family":"Kaliakatsos","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Ponnudas (Prab) Prabhakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Margrete B\u00f8en","family":"Keim","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital , Oslo , 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Neurobiol."},{"key":"2023020311103626600_ref3","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/ng.2599","article-title":"Mutations in DEPDC5 cause familial focal epilepsy with variable foci","volume":"45","author":"Dibbens","year":"2013","journal-title":"Nat. Genet."},{"key":"2023020311103626600_ref4","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/ng.2601","article-title":"Mutations of DEPDC5 cause autosomal dominant focal epilepsies","volume":"45","author":"Ishida","year":"2013","journal-title":"Nat. Genet."},{"key":"2023020311103626600_ref5","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1002\/ana.24368","article-title":"Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations","volume":"77","author":"Baulac","year":"2015","journal-title":"Ann. Neurol."},{"key":"2023020311103626600_ref6","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1002\/ana.24126","article-title":"Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations","volume":"75","author":"Scheffer","year":"2014","journal-title":"Ann. Neurol."},{"key":"2023020311103626600_ref7","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/acn3.191","article-title":"Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5","volume":"2","author":"Scerri","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"2023020311103626600_ref8","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2019.05.020","article-title":"Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals","volume":"105","author":"Epi25 Collaborative","year":"2019","journal-title":"Am. J. Hum. 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