{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:17:07Z","timestamp":1790806627745,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Health and Medical Research Council Program Grant","award":["1091593"],"award-info":[{"award-number":["1091593"]}]},{"name":"National Health and Medical Research Council Program Grant","award":["1129054"],"award-info":[{"award-number":["1129054"]}]},{"name":"National Health and Medical Research Council Program Grant","award":["1079058"],"award-info":[{"award-number":["1079058"]}]},{"name":"National Health and Medical Research Council Program Grant","award":["1006110"],"award-info":[{"award-number":["1006110"]}]},{"name":"National Health and Medical Research Council Program Grant","award":["1102971"],"award-info":[{"award-number":["1102971"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21-NS078657"],"award-info":[{"award-number":["R21-NS078657"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["TL1TR001875"],"award-info":[{"award-number":["TL1TR001875"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes\u2014DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15\/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline\/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.<\/jats:p>","DOI":"10.1093\/hmg\/ddab366","type":"journal-article","created":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T04:15:03Z","timestamp":1639714503000},"page":"2307-2316","source":"Crossref","is-referenced-by-count":21,"title":["Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6748-9651","authenticated-orcid":false,"given":"Timothy E","family":"Green","sequence":"first","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua E","family":"Motelow","sequence":"additional","affiliation":[{"name":"Institute for Genomic Medicine, Columbia University , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark F","family":"Bennett","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research , Melbourne, Victoria 3052 , Australia"},{"name":"Department of Medical Biology, University of Melbourne , Melbourne, Victoria 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimeng","family":"Ye","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole G","family":"Griffin","sequence":"additional","affiliation":[{"name":"Institute for Genomic Medicine, Columbia University , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Damiano","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J","family":"Leventer","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"},{"name":"Department of Paediatrics, University of Melbourne, Royal Children's Hospital , Parkville, VIC 3052 , Australia"},{"name":"Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy L","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"},{"name":"Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A Simon","family":"Harvey","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"},{"name":"Department of Paediatrics, University of Melbourne, Royal Children's Hospital , Parkville, VIC 3052 , Australia"},{"name":"Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J","family":"Lockhart","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University of Melbourne, Royal Children's Hospital , Parkville, VIC 3052 , Australia"},{"name":"Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynette G","family":"Sadleir","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, University of Otago , Wellington 6242 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Boys","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services , Parkville, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid E","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"Department of Neurology, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"},{"name":"Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"},{"name":"The Florey Institute of Neuroscience and Mental Health , Parkville, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Major","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Iowa , Iowa City, IA 52246 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin W","family":"Darbro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Iowa , Iowa City, IA 52246 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Bahlo","sequence":"additional","affiliation":[{"name":"Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research , Melbourne, Victoria 3052 , Australia"},{"name":"Department of Medical Biology, University of Melbourne , Melbourne, Victoria 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Institute for Genomic Medicine, Columbia University , New York, NY 10032 , USA"},{"name":"Department of Genetics and Development, Columbia University , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F","family":"Kerrigan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital , Phoenix, AZ 85013 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin L","family":"Heinzen","sequence":"additional","affiliation":[{"name":"Eshelman School of Pharmacy , Division of Pharmacotherapy and Experimental Therapeutics, and Department of Genetics, , Chapel Hill, NC 27599 , USA"},{"name":"University of North Carolina , Division of Pharmacotherapy and Experimental Therapeutics, and Department of Genetics, , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel F","family":"Berkovic","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"The University of Melbourne, Austin Health , Department of Medicine, , Heidelberg, VIC 3084 , Australia"},{"name":"Murdoch Children\u2019s Research Institute, The Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"2022072316184108000_ref1","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/ng0397-266","article-title":"GLI3 frameshift mutations cause autosomal dominant Pallister-hall syndrome","volume":"15","author":"Kang","year":"1997","journal-title":"Nat. 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Genet."},{"key":"2022072316184108000_ref4","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.ajhg.2016.05.031","article-title":"Mutations of the sonic hedgehog pathway underlie hypothalamic hamartoma with gelastic epilepsy","volume":"99","author":"Hildebrand","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"2022072316184108000_ref5","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1002\/acn3.300","article-title":"Somatic mutations in GLI3 and OFD1 involved in sonic hedgehog signaling cause hypothalamic hamartoma","volume":"3","author":"Saitsu","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"2022072316184108000_ref6","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1212\/01.wnl.0000284607.12906.c5","article-title":"Somatic mutations in GLI3 can cause hypothalamic hamartoma and gelastic seizures","volume":"70","author":"Wallace","year":"2008","journal-title":"Neurology"},{"key":"2022072316184108000_ref7","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/nature04117","article-title":"Vertebrate smoothened functions at the primary cilium","volume":"437","author":"Corbit","year":"2005","journal-title":"Nature"},{"key":"2022072316184108000_ref8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1371\/journal.pgen.0010053","article-title":"Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function","volume":"1","author":"Haycraft","year":"2005","journal-title":"PLoS Genet."},{"key":"2022072316184108000_ref9","doi-asserted-by":"crossref","first-page":"11325","DOI":"10.1073\/pnas.0505328102","article-title":"Cilia and hedgehog responsiveness in the mouse","volume":"102","author":"Huangfu","year":"2005","journal-title":"Proc. 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Genet."},{"key":"2022072316184108000_ref13","doi-asserted-by":"crossref","first-page":"e237","DOI":"10.1212\/WNL.0000000000007774","article-title":"Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma","volume":"93","author":"Fujita","year":"2019","journal-title":"Neurology"},{"key":"2022072316184108000_ref14","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/epi4.12378","article-title":"Repeat stereotactic radiofrequency thermocoagulation in patients with hypothalamic hamartoma and seizure recurrence","volume":"5","author":"Hiroshi","year":"2020","journal-title":"Epilepsia Open."},{"key":"2022072316184108000_ref15","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.seizure.2019.11.013","article-title":"Seizure outcome and prognostic factors for surgical management of hypothalamic hamartomas in children","volume":"75","author":"Ferrand-Sorbets","year":"2020","journal-title":"Seizure"},{"key":"2022072316184108000_ref16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.eplepsyres.2018.03.013","article-title":"MR-guided laser ablation for the treatment of hypothalamic hamartomas","volume":"142","author":"Curry","year":"2018","journal-title":"Epilepsy Res."},{"key":"2022072316184108000_ref17","first-page":"4774","article-title":"Subunit composition of the human cytoplasmic dynein-2 complex","volume":"127","author":"Asante","year":"2014","journal-title":"J. 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J. Hum. 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