De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. Issue 5 (27th February 2015)

• Record Type: Journal Article
• Authors: Blanchard, Maxime G; Willemsen, Marjolein H; Walker, Jaclyn B; Dib-Hajj, Sulayman D; Waxman, Stephen G; Jongmans, Marjolijn CJ; Kleefstra, Tjitske; van de Warrenburg, Bart P; Praamstra, Peter; Nicolai, Joost; Yntema, Helger G; Bindels, René JM; Meisler, Miriam H; Kamsteeg, Erik-Jan
• Is Part Of: Journal of medical genetics. Volume 52:Issue 5(2015)
• Page Start: 330
• Page End: 337
• Publication Date: 2015-02-27
• Subjects: Epilepsy and seizures -- Movement disorders (other than Parkinsons) -- intelectual disability -- sodium channel -- encephalopathy; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2014-102813
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV 1.6 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.