title: Epilepsy genetics: the ongoing revolution.
abstract: Epilepsies have long remained refractory to gene identification due to several obstacles, including a highly variable inter- and intrafamilial expressivity of the phenotypes, a high frequency of phenocopies, and a huge genetic heterogeneity. Recent technological breakthroughs, such as array comparative genomic hybridization and next generation sequencing, have been leading, in the past few years, to the identification of an increasing number of genomic regions and genes in which mutations or copy-number variations cause various epileptic disorders, revealing an enormous diversity of pathophysiological mechanisms. The field that has undergone the most striking revolution is that of epileptic encephalopathies, for which most of causing genes have been discovered since the year 2012. Some examples are the continuous spike-and-waves during slow-wave sleep and Landau-Kleffner syndromes for which the recent discovery of the role of GRIN2A mutations has finally confirmed the genetic bases. These new technologies begin to be used for diagnostic applications, and the main challenge now resides in the interpretation of the huge mass of variants detected by these methods. The identification of causative mutations in epilepsies provides definitive confirmation of the clinical diagnosis, allows accurate genetic counselling, and sometimes permits the development of new appropriate and specific antiepileptic therapies. Future challenges include the identification of the genetic or environmental factors that modify the epileptic phenotypes caused by mutations in a given gene and the understanding of the role of somatic mutations in sporadic epilepsies.
authors.affiliation: Service de génétique, groupement hospitalier Est, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron, France; Université Claude-Bernard Lyon 1, 43, boulevard du 11-Novembre-1918, 69100 Villeurbanne, France; CRNL, CNRS UMR 5292, Inserm U1028, bâtiment IMBL, 11, avenue Jean-Capelle, 69621 Villeurbanne cedex, France. Electronic address: gaetan.lesca@chu-lyon.fr.
authors.forename: G
authors.initials: G
authors.lastname: Lesca
authors.affiliation: Département de génétique et cytogénétique, hôpital Pitié-Salpêtrière, AP-HP, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France; Sorbonne universités, UPMC université Paris 06, 4, place Jussieu, 75005 Paris, France; ICM, CNRS UMR 7225, Inserm U1127, 47, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: C
authors.initials: C
authors.lastname: Depienne
mesh_terms: D000328:Adult; D002648:Child; D004831:Epilepsies, Myoclonic / Q000235:genetics; D004828:Epilepsies, Partial / Q000235:genetics; D004827:Epilepsy / Q000235:genetics*; D018628:Gene Dosage; D014644:Genetic Variation; D006801:Humans
keywords: Copy-number variation; Encéphalopathie épileptique; Epilepsy; Epileptic encephalopathy; Gene; Genetics; Gène; Génétique; Variations du nombre de copies; Épilepsie