title: Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR.
abstract: OBJECTIVE
  To define causative somatic mutations in resected brain tissue from an infant with intractable epilepsy secondary to hemispheric cortical dysplasia.
  
  
  METHODS
  Whole-exome sequencing was conducted on genomic DNA derived from both resected brain tissue and peripheral blood leukocytes. Comparison of the brain vs blood sequencing results was performed using bioinformatic methods designed to detect low-frequency genetic variation between tissue pairs.
  
  
  RESULTS
  Histopathology of the resected tissue showed dyslamination and dysmorphic neurons, but no balloon cells, consistent with focal cortical dysplasia type IIa. mTOR activation was observed by immunohistochemistry in the dysplasia. A missense mutation (c.4487T>G; p.W1456G) was detected in the FAT domain of MTOR in DNA from the dysplasia but not in lymphocytes. The mutation is predicted damaging (i.e., leading to mTOR activation) and was observed as a low-level mosaic with 8% of cells being heterozygous for the variant.
  
  
  CONCLUSIONS
  We report the novel finding of an MTOR mutation associated with nonsyndromic cortical dysplasia. Somatic-specific mutations in MTOR and related genes should be considered in a broader spectrum of patients with hemispheric malformations and more restricted forms of cortical dysplasia.
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA. richard.leventer@rch.org.au.
authors: Richard J
authors: RJ
authors: Leventer
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Thomas
authors: T
authors: Scerri
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Ashley P L
authors: AP
authors: Marsh
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Kate
authors: K
authors: Pope
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Greta
authors: G
authors: Gillies
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Wirginia
authors: W
authors: Maixner
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Duncan
authors: D
authors: MacGregor
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: A Simon
authors: AS
authors: Harvey
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Martin B
authors: MB
authors: Delatycki
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: David J
authors: DJ
authors: Amor
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Peter
authors: P
authors: Crino
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Melanie
authors: M
authors: Bahlo
authors: From the Departments of Neurology (R.J.L., A.S.H.), Neurosurgery (W.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Melbourne; Department of Pediatrics (R.J.L., A.S.H., M.B.D., D.J.A., P.J.L.), The University of Melbourne; Bioinformatics Division (T.S., M.B.), The Walter and Eliza Hall Institute of Medical Research, Melbourne; Bruce Lefroy Centre for Genetic Health Research (A.P.L.M., K.P., G.G., M.B.D., D.J.A., P.J.L.), Murdoch Childrens Research Institute (R.J.L., A.S.H.), Melbourne; Clinical Genetics (M.B.D.), Austin Health, Melbourne, Australia; and Shriners Hospital Pediatric Research Center (P.C.), Temple University, Philadelphia, PA.
authors: Paul J
authors: PJ
authors: Lockhart
mesh_terms: D001921:Brain / Q000473:pathology; D004827:Epilepsy / Q000209:etiology; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D054220:Malformations of Cortical Development / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D020125:Mutation, Missense; D009474:Neurons / Q000473:pathology; D049268:Positron-Emission Tomography; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases