title: Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.forename: Sinéad B
authors.initials: SB
authors.lastname: Heavin
authors.forename: Simone C
authors.initials: SC
authors.lastname: Yendle
authors.forename: Jacinta M
authors.initials: JM
authors.lastname: McMahon
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.forename: Joseph
authors.initials: J
authors.lastname: Cook
authors.forename: Adiba
authors.initials: A
authors.lastname: Khan
authors.forename: Michael O
authors.initials: MO
authors.lastname: Dorschner
authors.forename: Molly
authors.initials: M
authors.lastname: Weaver
authors.forename: Sophie
authors.initials: S
authors.lastname: Calvert
authors.forename: Stephen
authors.initials: S
authors.lastname: Malone
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wallace
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stanley
authors.forename: Ann M E
authors.initials: AM
authors.lastname: Bye
authors.forename: Andrew
authors.initials: A
authors.lastname: Bleasel
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Howell
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.forename: Mark T
authors.initials: MT
authors.lastname: Mackay
authors.forename: Victoria
authors.initials: V
authors.lastname: Rodriguez-Casero
authors.forename: Richard
authors.initials: R
authors.lastname: Webster
authors.forename: Amos
authors.initials: A
authors.lastname: Korczyn
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.forename: Nathanel
authors.initials: N
authors.lastname: Zelnick
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.forename: Deepak
authors.initials: D
authors.lastname: Gill
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Andrade
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Freeman
authors.forename: Lynette G
authors.initials: LG
authors.lastname: Sadleir
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000502:physiology; D055815:Young Adult; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
chemical_list: C575189:CHD2 protein, human; D004268:DNA-Binding Proteins; C484739:SYNGAP1 protein, human; D020703:ras GTPase-Activating Proteins