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Identification of a somatic mutation in the RHEB gene through high depth and ultra-high depth next generation sequencing in a patient with Hemimegalencephaly and drug resistant Epilepsy.

Authors
  • Salinas, Valeria1
  • Vega, Patricia2
  • Piccirilli, María Victoria3
  • Chicco, Carla3
  • Ciraolo, Carlos4
  • Christiansen, Silvia5
  • Consalvo, Damián6
  • Perez-Maturo, Josefina1
  • Medina, Nancy7
  • González-Morón, Dolores7
  • Novaro, Virginia8
  • Perrone, Cecilia8
  • García, María Del Carmen9
  • Agosta, Guillermo3
  • Silva, Walter3
  • Kauffman, Marcelo10
  • 1 Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología y División Neurología, Hospital José María Ramos Mejía, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Programa de Medicina de Precisión y Genómica Clínica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Buenos Aires, Argentina. , (Argentina)
  • 2 Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología y División Neurología, Hospital José María Ramos Mejía, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Servicio de Neurología Infantil, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. , (Argentina)
  • 3 Servicio de Neurología Infantil, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. , (Argentina)
  • 4 Servicio de Neurocirugía, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. , (Argentina)
  • 5 Servicio de Anatomía Patológica, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. , (Argentina)
  • 6 División Neurología, Hospital José María Ramos Mejía, Facultad de Medicina, Universidad de Buenos Aires, Argentina. , (Argentina)
  • 7 Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología y División Neurología, Hospital José María Ramos Mejía, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. , (Argentina)
  • 8 Laboratorio de Proteínas Quinasas y Cáncer, IBYME, Buenos Aires, Argentina. , (Argentina)
  • 9 Servicio de Neurología de Adultos, Hospital Italiano de Buenos Aires, Argentina. , (Argentina)
  • 10 Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología y División Neurología, Hospital José María Ramos Mejía, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Programa de Medicina de Precisión y Genómica Clínica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Buenos Aires, Argentina. Electronic address: [email protected] , (Argentina)
Type
Published Article
Journal
European journal of medical genetics
Publication Date
Nov 01, 2019
Volume
62
Issue
11
Pages
103571–103571
Identifiers
DOI: 10.1016/j.ejmg.2018.11.005
PMID: 30414531
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Malformations of cortical development are a frequent cause of drug-resistant Epilepsy and developmental delay. Hemimegalencephaly is a Malformation of cortical development characterized by enlargement of all or a part of one cerebral hemisphere. Germline and somatic mutation in genes belonging to the Mammalian Target of Rapamycin (mTOR) pathway has been identified in patients suffering from epilepsy secondary to Hemimegalencephaly and focal cortical dysplasia. We present here a patient suffering from severe neonatal Epilepsy since 3 h of life secondary to Hemimegalencephaly, requiring an anatomic hemispherectomy surgical procedure for seizure control, where by means of next-generation sequencing at an ultra-high depth coverage, we were able to identify a novel somatic mutation in the RHEB gene (NM_005614: c.119A > T: p. Glu40Val). The histopathological diagnosis was Cortical Dysplasia type IIB determined by the presence of dysmorphic neurons of variable size with nuclear alteration and balloon cells in the context of Hemimegalencephaly, which are similar to that have been demonstrated in hyperactivating RHEB models. This is the first report of a somatic mutation in RHEB gene in a patient suffering from Epilepsy secondary to Hemimegalencephaly. It highlights different current topics in the fields of genetics of Malformations of cortical development: a-somatic mosaicism is not uncommon in these neurodevelopmental disorders; b-the molecular diagnostic approach should involve the use of state-of-the-art methods and the sampling of different tissues; c-new findings might facilitate therapeutics discoveries while providing an improved understanding of normal brain development. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

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