Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16169
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dc.contributor.authorHildebrand, Michael S-
dc.contributor.authorGriffin, Nicole G-
dc.contributor.authorDamiano, John A-
dc.contributor.authorCops, Elisa J-
dc.contributor.authorBurgess, Rosemary-
dc.contributor.authorOzturk, Ezgi-
dc.contributor.authorJones, Nigel C-
dc.contributor.authorLeventer, Richard J-
dc.contributor.authorFreeman, Jeremy L-
dc.contributor.authorHarvey, A Simon-
dc.contributor.authorSadleir, Lynette G-
dc.contributor.authorScheffer, Ingrid E-
dc.contributor.authorMajor, Heather-
dc.contributor.authorDarbro, Benjamin W-
dc.contributor.authorAllen, Andrew S-
dc.contributor.authorGoldstein, David B-
dc.contributor.authorKerrigan, John F-
dc.contributor.authorBerkovic, Samuel F-
dc.contributor.authorHeinzen, Erin L-
dc.date2016-07-21-
dc.date.accessioned2016-08-26T02:03:05Z-
dc.date.available2016-08-26T02:03:05Z-
dc.date.issued2016-08-04-
dc.identifier.citationAmerican Journal of Human Genetics 2016; 99(2): 423-429en_US
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/16169-
dc.description.abstractHypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.en_US
dc.titleMutations of the sonic hedgehog pathway underlie hypothalamic hamartoma with gelastic epilepsyen_US
dc.typeJournal Articleen_US
dc.identifier.journaltitleAmerican Journal of Human Geneticsen_US
dc.identifier.affiliationAustin Health, Heidelberg, Victoria, Australiaen_US
dc.identifier.affiliationEpilepsy Research Center, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australiaen_US
dc.identifier.affiliationInstitute for Genomic Medicine, Columbia University, New York, NY, USAen_US
dc.identifier.affiliationDepartment of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, Australiaen_US
dc.identifier.affiliationDepartment of Neurology, The Royal Children’s Hospital, Parkville, Victoria, Australiaen_US
dc.identifier.affiliationDepartment of Paediatrics, University of Melbourne, The Royal Children’s Hospital, Parkville, Victoria, Australiaen_US
dc.identifier.affiliationMurdoch Childrens Research Institute, The Royal Children’s Hospital, Parkville, Victoria, Australiaen_US
dc.identifier.affiliationDepartment of Paediatrics and Child Health, University of Otago, Wellington, New Zealanden_US
dc.identifier.affiliationThe Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australiaen_US
dc.identifier.affiliationDepartment of Pediatrics, The University of Iowa, Iowa City, IA, USAen_US
dc.identifier.affiliationDepartment of Biostatistics and Bioinformatics, Duke University, Durham, NC, USAen_US
dc.identifier.affiliationDivision of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, USAen_US
dc.identifier.affiliationDepartment of Pathology and Cell Biology, Columbia University, New York, NY, USAen_US
dc.identifier.pubmedurihttps://pubmed.ncbi.nlm.nih.gov/27453577en_US
dc.identifier.doi10.1016/j.ajhg.2016.05.031en_US
dc.type.contentTexten_US
dc.identifier.orcid0000-0002-2311-2174en_US
dc.identifier.orcid0000-0003-4580-841Xen_US
dc.type.austinJournal Articleen_US
local.name.researcherBerkovic, Samuel F
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.openairetypeJournal Article-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptMedicine (University of Melbourne)-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptNeurology-
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