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.

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.

• Authors: Valeria Salinas, Patricia Vega, María Victoria Piccirilli, Carla Chicco, Carlos Ciraolo, Silvia Christiansen, Damián Consalvo, Josefina Perez-Maturo, Nancy Medina, Dolores González-Morón, Virginia Novaro, Cecilia Perrone, María Del Carmen García, Guillermo Agosta, Walter Silva, Marcelo Kauffman
• Journal: European journal of medical genetics (Eur J Med Genet) Vol. 62 Issue 11 Pg. 103571 (Nov 2019) ISSN: 1878-0849 [Electronic] Netherlands
• PMID: 30414531 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• RHEB protein, human
• Ras Homolog Enriched in Brain Protein
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Drug Resistant Epilepsy (genetics, pathology)
• Female
• Hemimegalencephaly (genetics, pathology)
• High-Throughput Nucleotide Sequencing
• Humans
• Infant, Newborn
• Malformations of Cortical Development (genetics, pathology)
• Mutation
• Ras Homolog Enriched in Brain Protein (genetics)
• TOR Serine-Threonine Kinases (genetics)