Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions
| العنوان: | Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions |
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| المؤلفون: | Timothy E Green, Joshua E Motelow, Mark F Bennett, Zimeng Ye, Caitlin A Bennett, Nicole G Griffin, John A Damiano, Richard J Leventer, Jeremy L Freeman, A Simon Harvey, Paul J Lockhart, Lynette G Sadleir, Amber Boys, Ingrid E Scheffer, Heather Major, Benjamin W Darbro, Melanie Bahlo, David B Goldstein, John F Kerrigan, Erin L Heinzen, Samuel F Berkovic, Michael S Hildebrand |
| المصدر: | Hum Mol Genet |
| بيانات النشر: | Oxford University Press (OUP), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | congenital, hereditary, and neonatal diseases and abnormalities, Hamartoma, Genetics, Humans, Original Article, Hedgehog Proteins, General Medicine, Magnetic Resonance Imaging, Molecular Biology, Ciliopathies, Hypothalamic Diseases, Genetics (clinical) |
| الوصف: | 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. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c335523fad181bfe5a044bcac20cd8eTest https://doi.org/10.1093/hmg/ddab366Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3c335523fad181bfe5a044bcac20cd8e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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