title: Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum.
abstract: Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Rosemary
authors.identifier: 0000-0002-2664-4395
authors.initials: R
authors.lastname: Burgess
authors.affiliation: Department of Pediatric Neurology and Epilepsy Center, Schneider Children's Medical Center of Israel, Petah Tiqva, Israel.|Pediatric Neurology Unit, Epilepsy Clinic, Wolfson Medical Center, Holon, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.affiliation: Pediatric Neurology Unit, Epilepsy Clinic, Wolfson Medical Center, Holon, Israel.
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.affiliation: Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.|Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001037:Aphasia / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D005192:Family Health; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012890:Sleep / Q000502:physiology; D013036:Spasms, Infantile / Q000235:genetics* / Q000503:physiopathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C479421:CNKSR2 protein, human
keywords: 
  CNKSR2
  ; Developmental delay; Epilepsy-aphasia spectrum; Sanger sequencing; Speech delay