title: Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia.
abstract: Focal malformations of cortical development, including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are important causes of intractable childhood epilepsy. Using targeted and exome sequencing on DNA from resected brain samples and nonbrain samples from 53 patients with FCD or HME, we identified pathogenic germline and mosaic mutations in multiple PI3K/AKT pathway genes in 9 patients, and a likely pathogenic variant in 1 additional patient. Our data confirm the association of DEPDC5 with sporadic FCD but also implicate this gene for the first time in HME. Our findings suggest that modulation of the mammalian target of rapamycin pathway may hold promise for malformation-associated epilepsy.
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: D'Gama
authors.forename: Ying
authors.initials: Y
authors.lastname: Geng
authors.forename: Javier A
authors.initials: JA
authors.lastname: Couto
authors.forename: Beth
authors.initials: B
authors.lastname: Martin
authors.forename: Evan A
authors.initials: EA
authors.lastname: Boyle
authors.forename: Christopher M
authors.initials: CM
authors.lastname: LaCoursiere
authors.forename: Amer
authors.initials: A
authors.lastname: Hossain
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Hatem
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Barry
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Gary W
authors.initials: GW
authors.lastname: Mathern
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
mesh_terms: D015331:Cohort Studies; D020690:GTPase-Activating Proteins; D065705:Hemimegalencephaly / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D054220:Malformations of Cortical Development / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D020690:GTPase-Activating Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; C000590398:DEPDC5 protein, human; C546842:MTOR protein, human