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Title: Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions.
Austin Authors: Green, Timothy E;Motelow, Joshua E;Bennett, Mark F ;Ye, Zimeng;Bennett, Caitlin A;Griffin, Nicole G;Damiano, John A;Leventer, Richard J;Freeman, Jeremy L;Harvey, A Simon;Lockhart, Paul J;Sadleir, Lynette G;Boys, Amber;Scheffer, Ingrid E ;Major, Heather;Darbro, Benjamin W;Bahlo, Melanie;Goldstein, David B;Kerrigan, John F;Heinzen, Erin L;Berkovic, Samuel F ;Hildebrand, Michael S 
Affiliation: Epilepsy Research Centre
The Florey Institute of Neuroscience and Mental Health
Institute for Genomic Medicine, Columbia University, New York, New York, 10032, USA
Department of Pediatrics, The University of Iowa, Iowa, 52246, USA
Department of Genetics and Development, Columbia University, New York, New York, 10032, USA
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, 3052, Australia
Victorian Clinical Genetics Services, Parkville, 3052, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, 3052, Australia
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, 3052, Australia
Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona 85013, USA
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
Department of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand
Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, and Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, 27599, USA
Issue Date: 21-Jul-2022 2022
Publication information: Human Molecular Genetics 2022; 31(14): 2307-2316
Abstract: 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 localise 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-DYNC2I1, 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 re-conceptualize the disorder as a ciliopathy.
DOI: 10.1093/hmg/ddab366
ORCID: 0000-0002-6748-9651
PubMed URL: 35137044
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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