title: Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation.
abstract: We present a 4-year-old girl with profound global developmental delay and refractory epilepsy characterized by multiple seizure types (partial complex with secondary generalization, tonic, myoclonic, and atypical absence). Her seizure semiology did not fit within a specific epileptic syndrome. Despite a broad metabolic and genetic workup, a diagnosis was not forthcoming. Whole-exome sequencing with a trio analysis (affected child compared to unaffected parents) was performed and identified a novel de novo missense mutation in GRIN2A, c.2449A>G, p.Met817Val, as the likely cause of the refractory epilepsy and global developmental delay. GRIN2A encodes a subunit of N-methyl-d-aspartate (NMDA) receptor that mediates excitatory transmission in the central nervous system. A significant reduction in the frequency and the duration of her seizures was observed after the addition of topiramate over a 10-month period. Further prospective studies in additional patients with mutations in GRIN2A will be required to optimize seizure management for this rare disorder. This report expands the current phenotype associated with GRIN2A mutations.
authors.affiliation: Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Sunita
authors.initials: S
authors.lastname: Venkateswaran
authors.forename: Ken A
authors.initials: KA
authors.lastname: Myers
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Smith
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Dennis
authors.initials: D
authors.lastname: Bulman
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
mesh_terms: D002675:Child, Preschool; D002658:Developmental Disabilities / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D004827:Epilepsy / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: Developmental delay; Epilepsy; GRIN2A; Gamma-aminobutyric acid (GABA) receptor; Personalized medicine; Topiramate; Whole-exome sequencing