Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions.

Ciliopathies / genetics Hamartoma / genetics Hedgehog Proteins / metabolism Humans Hypothalamic Diseases / complications Magnetic Resonance Imaging

Journal

Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958

Informations de publication

Date de publication:
21 07 2022
Historique:
received: 04 11 2021
revised: 02 12 2021
accepted: 15 12 2021
pubmed: 10 2 2022
medline: 27 7 2022
entrez: 9 2 2022
Statut: ppublish

Résumé

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-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 reconceptualize the disorder as a ciliopathy.

Identifiants

DOI: 10.1093/hmg/ddab366 PMID: 35137044 PMC: PMC9307310
pubmed: 35137044
pii: 6524341
doi: 10.1093/hmg/ddab366
pmc: PMC9307310
doi:

Substances chimiques

Hedgehog Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2307-2316

Subventions

Organisme : NIH HHS
ID : R21-NS078657
Pays : United States

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Auteurs

Timothy E Green (TE)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
ORCID: 0000-0002-6748-9651

Joshua E Motelow (JE)

Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.

Mark F Bennett (MF)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.

Zimeng Ye (Z)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.

Caitlin A Bennett (CA)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.

Nicole G Griffin (NG)

Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.

John A Damiano (JA)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.

Richard J Leventer (RJ)

Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.

Jeremy L Freeman (JL)

Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.

A Simon Harvey (AS)

Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.

Paul J Lockhart (PJ)

Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.

Lynette G Sadleir (LG)

Department of Paediatrics and Child Health, University of Otago, Wellington 6242, New Zealand.

Amber Boys (A)

Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia.

Ingrid E Scheffer (IE)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia.

Heather Major (H)

Department of Pediatrics, The University of Iowa, Iowa City, IA 52246, USA.

Benjamin W Darbro (BW)

Department of Pediatrics, The University of Iowa, Iowa City, IA 52246, USA.

Melanie Bahlo (M)

Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.

David B Goldstein (DB)

Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
Department of Genetics and Development, Columbia University, New York, NY 10032, USA.

John F Kerrigan (JF)

Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85013, USA.

Erin L Heinzen (EL)

Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, and Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.

Samuel F Berkovic (SF)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.

Michael S Hildebrand (MS)

Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.

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Classifications MeSH

questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Ciliopathies › Sporadic hypothalamic hamartoma is a...
questionsmedicales.fr › Tumeurs › Hamartomes › Sporadic hypothalamic hamartoma is a...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines Hedgehog › Sporadic hypothalamic hamartoma is a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Sporadic hypothalamic hamartoma is a...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Maladies hypothalamiques › Sporadic hypothalamic hamartoma is a...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Imagerie diagnostique › Tomographie › Imagerie par résonance magnétique › Sporadic hypothalamic hamartoma is a...