TY - JOUR T1 - De novo gain-of-function and loss-of-function mutations of <em>SCN8A</em> in patients with intellectual disabilities and epilepsy JF - Journal of Medical Genetics JO - J Med Genet SP - 330 LP - 337 DO - 10.1136/jmedgenet-2014-102813 VL - 52 IS - 5 AU - Maxime G Blanchard AU - Marjolein H Willemsen AU - Jaclyn B Walker AU - Sulayman D Dib-Hajj AU - Stephen G Waxman AU - Marjolijn CJ Jongmans AU - Tjitske Kleefstra AU - Bart P van de Warrenburg AU - Peter Praamstra AU - Joost Nicolai AU - Helger G Yntema AU - René JM Bindels AU - Miriam H Meisler AU - Erik-Jan Kamsteeg Y1 - 2015/05/01 UR - http://jmg.bmj.com/content/52/5/330.abstract N2 - Background Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. Methods The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype–phenotype correlations of these and other cases were related to the functional analyses. Results The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. Conclusions Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing. ER -