Journal article
Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions
Human molecular genetics, Vol.31(14), pp.2307-2316
07/21/2022
DOI: 10.1093/hmg/ddab366
PMCID: PMC9307310
PMID: 35137044
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 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.
Details
- Title: Subtitle
- Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions
- Creators
- Timothy E. Green - Austin HealthJoshua E. Motelow - Columbia UniversityMark F. Bennett - Austin HealthZimeng Ye - Austin HealthCaitlin A. Bennett - Austin HealthNicole G. Griffin - Columbia UniversityJohn A. Damiano - Austin HealthRichard J. Leventer - Royal Children's HospitalJeremy L. Freeman - Royal Children's HospitalA. Simon Harvey - Royal Children's HospitalPaul J. Lockhart - Royal Children's HospitalLynette G. Sadleir - University of OtagoAmber Boys - Victorian Clinical Genetics ServicesIngrid E. Scheffer - Austin HealthHeather Major - University of IowaBenjamin W. Darbro - University of IowaMelanie Bahlo - Walter and Eliza Hall Institute of Medical ResearchDavid B. Goldstein - Columbia UniversityJohn F. Kerrigan - Barrow Neurological InstituteErin L. Heinzen - University of North Carolina at Chapel HillSamuel F. Berkovic - Austin HealthMichael S. Hildebrand - Austin Health
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.31(14), pp.2307-2316
- Publisher
- Oxford Univ Press
- DOI
- 10.1093/hmg/ddab366
- PMID
- 35137044
- PMCID
- PMC9307310
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Number of pages
- 10
- Grant note
- Perpetual Charitable Trustees University of Melbourne Australian Postgraduate Award International Graduate Research Training Scholarship R21-NS078657; TL1TR001875 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA March of Dimes Australian Government NHMRC IRIISS; National Health and Medical Research Council (NHMRC) of Australia National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Tang Lixin Education Development Fund Victorian State Government Operational Infrastructure Support US Department of Defense Autism Spectrum Disorder Research Program; United States Department of Defense CURE Taking Flight Award from CURE Epilepsy Melbourne Children's Clinician Scientist Fellowship Health Research Council of NewZealand; Health Research Council of New Zealand Australian Research Council American Epilepsy Society Vincent Ciodo Foundation 3576 / CureKids 15/070 project grant 1091593; 1129054; 1079058; 1006110; 1102971; 1063799 / National Health and Medical Research Council; National Health and Medical Research Council (NHMRC) of Australia
- Language
- English
- Date published
- 07/21/2022
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984354053502771
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