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

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.Fil: Salinas Calderon, Valeria Macarena. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Vega, Liliana Patricia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Piccirilli, María Victoria.Fil: Chicco, Carla.Fil: Ciraolo, Carlos.Fil: Christiansen, Silvia Beatriz.Fil: Consalvo, Damian.Fil: Perez Maturo, Josefina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Medina, Nancy. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: González Morón, Dolores. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Novaro, Virginia.Fil: Perrone, Maria Cecilia.Fil: García, María del Carmen.Fil: Agosta, Guillermo.Fil: Silva, Walter.Fil: Kauffman, Marcelo Andres. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentin