Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum

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 epilepsyaphasia 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 epilepsywith centrotemporal spikes. Thismutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of pointmutation is low, CNKSR2 sequencing should be considered in families with suspectedX-linked EAS because of the specific genetic counseling implications.