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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.01135

Rare variants in 48 genes account for 42% of cases of epilepsy with or without neurodevelopmental delay in 246 paediatric patients

 Ana Fernandez-Marmiesse1, 2*,  Iria Roca1, 2,  Felícitas Díaz Flores3,  Verónica Cantarín4,  María S. Pérez-Poyato5, Ana Fontalba6,  Francisco Laranjeira7,  Sofia Quintas8,  Oana Moldovan9, Blanca Felgueroso10, Montserrat Rodríguez-Pereira11, Rogelio Simón12, Ana Camacho12, 13,  Pilar Quijada-Fraile14,  Salvador Ibáñez15,  Rosario Domingo16, María C. Benito17,  Rocío Calvo18,  Antonia M. Pérez-Cejas3, María L. Carrasco-Marina19,  Feliciano J. Ramos20, 21,  María L. Couce22, María L. Ruiz-Falco4,  Luis Gutiérrez-Solana4 and Margarita Martínez-Atienza23
  • 1Sanitary Research Institute Foundation of Santiago de Compostela, Spain
  • 2Genomes&Disease Group, Molecular Medicine and Chronic Diseases Research Centre (CiMUS), University of Santiago de Compostela, Spain
  • 3Unidad de Diagnóstico Molecular. Hospital Universitario de Canarias. Santa Cruz de Tenerife, Spain
  • 4Neuropediatrics, Niño Jesús University Children's Hospital, Spain
  • 5Pediatric Neurology Unit, Department of Pediatrics, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain., Spain
  • 6Department of Genetics, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain, Spain
  • 7Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, Portugal
  • 8Neuropediatrics, Hospital of Santa Maria, University Hospital Center Lisbon Norte, Portugal
  • 9Clinical Genetics, Hospital of Santa Maria, University Hospital Center Lisbon Norte, Portugal
  • 10Neuropediatría. Hospital Materno-Infantil. A Coruña., Spain
  • 11Department of Clinical Genetics, University of A Coruña, Spain
  • 12Department of Neurology, University Hospital October 12, Spain
  • 13Faculty of Medicine, Complutense University of Madrid, Spain
  • 14Unidad de Enfermedades Mitocondriales y Metabólicas Hereditarias. Hospital Universitario 12 de Octubre. Madrid., Spain
  • 15Neuropediatría, Hospital Universitario Virgen de la Arrixaca, Spain
  • 16Hospital Universitario Virgen de la Arrixaca, Spain
  • 17Genetics department, Hospital Regional Universitario de Malaga, Spain
  • 18Neuropediatrics, Hospital Regional Universitario de Malaga, Spain
  • 19Neuropediatría, Hospital Universitario Severo Ochoa. Leganés, Madrid, Spain
  • 20Facultad de Medicina, University of Zaragoza, Spain
  • 21Unidad de Genética Clínica, Pediatric Service, Lozano Blesa University Clinical Hospital, Spain
  • 22Neonatology Unit, Sanitary Research Institute Foundation of Santiago de Compostela, Spain
  • 23Virgen de las Nieves University Hospital, Spain

In order to characterize the genetic architecture of epilepsy in a paediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counselling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for nondiagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.

Keywords: Epilepsy, diagnosis, Neurodevelopmental disorders, Incomplete penetrance, De novo mutations

Received: 21 Jun 2019; Accepted: 08 Oct 2019.

Copyright: © 2019 Fernandez-Marmiesse, Roca, Díaz Flores, Cantarín, Pérez-Poyato, Fontalba, Laranjeira, Quintas, Moldovan, Felgueroso, Rodríguez-Pereira, Simón, Camacho, Quijada-Fraile, Ibáñez, Domingo, Benito, Calvo, Pérez-Cejas, Carrasco-Marina, Ramos, Couce, Ruiz-Falco, Gutiérrez-Solana and Martínez-Atienza. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ana Fernandez-Marmiesse, Sanitary Research Institute Foundation of Santiago de Compostela, Santiago de Compostela, 15706, Galicia, Spain,