Gene

Internal medicine

Phenotype

Exome sequencing

Neuroscience

Epilepsy

Disease

Genetic testing

Mutation

Genetics

Bioinformatics

Medicine

Sanger sequencing

Biology

Neurology

<h3>Objective</h3> To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset <i>KCNT1</i> epilepsy. <h3>Methods</h3> We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in <i>KCNT1</i> using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified <i>KCNT1</i> variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a <i>xenopus</i> oocyte model system. <h3>Results</h3> We identified pathogenic variants in <i>KCNT1</i> in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated <i>KCNT1</i> variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. <h3>Conclusions</h3> Gain-of-function <i>KCNT1</i> pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

Clinical and molecular characterization of <i>KCNT1</i> -related severe early-onset epilepsy

Clinical and molecular characterization of KCNT1 -related severe early-onset epilepsy