title: Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy.
abstract: Hypothalamic 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.
authors.affiliation: Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Griffin
authors.affiliation: Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia.
authors.forename: Elisa J
authors.initials: EJ
authors.lastname: Cops
authors.affiliation: Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burgess
authors.affiliation: Department of Medicine, The University of Melbourne and The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors.forename: Ezgi
authors.initials: E
authors.lastname: Ozturk
authors.affiliation: Department of Medicine, The University of Melbourne and The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
authors.affiliation: Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne and The Royal Children's Hospital, Parkville, VIC 3052, Australia; Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Freeman
authors.affiliation: Department of Neurology, The Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne and The Royal Children's Hospital, Parkville, VIC 3052, Australia; Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors.forename: A Simon
authors.initials: AS
authors.lastname: Harvey
authors.affiliation: Department of Paediatrics and Child Health, University of Otago, Wellington 9016, New Zealand.
authors.forename: Lynette G
authors.initials: LG
authors.lastname: Sadleir
authors.affiliation: Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia; Department of Paediatrics, University of Melbourne and The Royal Children's Hospital, Parkville, VIC 3052, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA 52246, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Major
authors.affiliation: Department of Pediatrics, The University of Iowa, Iowa City, IA 52246, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Allen
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.affiliation: Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85013, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Kerrigan
authors.affiliation: Epilepsy Research Center, Department of Medicine, The University of Melbourne and Austin Health, Heidelberg, VIC 3084, Australia. Electronic address: s.berkovic@unimelb.edu.au.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: eh2682@cumc.columbia.edu.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
mesh_terms: D050882:CREB-Binding Protein / Q000235:genetics; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics; D004828:Epilepsies, Partial / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006222:Hamartoma / Q000235:genetics*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007027:Hypothalamic Diseases / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: C082593:GLI2 protein, human; C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C509239:SHH protein, human; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human