Abstracts

Rationale: Synaptic proteins are critical to neuronal function in the brain and their deficiency can lead to seizures and cognitive impairments. CNKSR2 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 language, intellectual and attention deficits. Methods: In this study we sequenced 123 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) and possible X-linked inheritance to determine the frequency of CNKSR2 mutation within this complex spectrum of disorders. Results: We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with a less severe phenotype, while their sister had childhood epilepsy with centro-temporal spikes and a mild learning disability. This mutation segregated in the three affected siblings in an X-linked dominant manner, inherited from their mother who had febrile seizures. Conclusions: Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the self-limiting nature of the phenotype and specific genetic counseling implications. Funding: This study was supported by National Health and Medical Research Council Program Grant (628952) to S.F.B and I.E.S, a Practitioner Fellowship (1006110) to I.E.S and a R.D Wright Career Development Fellowship (1063799) to M.S.H.