Carvill, Gemma L2; Heavin, Sinéad B2; Yendle, Simone C2; McMahon, Jacinta M2; O'Roak, Brian J2; Cook, Joseph2; Khan, Adiba2; Dorschner, Michael O2; Weaver, Molly2; Calvert, Sophie2; Malone, Stephen2; Wallace, Geoffrey2; Stanley, Thorsten2; Bye, Ann M E2; Bleasel, Andrew2; Howell, Katherine B2; Kivity, Sara2; Mackay, Mark T2; Rodriguez-Casero, Victoria2; Webster, Richard2; Korczyn, Amos2; Afawi, Zaid2; Zelnick, Nathanel2; Lerman-Sagie, Tally2; Lev, Dorit2; Møller, Rikke S3; Gill, Deepak2; Andrade, Danielle M2; Freeman, Jeremy L2; Sadleir, Lynette G2; Shendure, Jay2; Berkovic, Samuel F2; Scheffer, Ingrid E2; Mefford, Heather C2
1 Danish Epilepsy Centre, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU2 unknown3 Danish Epilepsy Centre, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU
Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.
Nature Genetics, 2013, Vol 45, Issue 7, p. 825-30
Adolescent; Adult; Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; DNA-Binding Proteins; Epilepsy; Female; Genetic Predisposition to Disease; Humans; Male; Mutation; Young Adult; ras GTPase-Activating Proteins