Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.

TitleExome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.
Publication TypeJournal Article
Year of Publication2011
AuthorsKlassen, T, Davis, C, Goldman, A, Burgess, D, Chen, T, Wheeler, DA, McPherson, J, Bourquin, T, Lewis, L, Villasana, D, Morgan, M, Muzny, DM, Gibbs, RA, Noebels, J
JournalCell
Volume145
Issue7
Pagination1036-48
Date Published2011 Jun 24
ISSN1097-4172
KeywordsComputer Simulation, Epilepsy, Epistasis, Genetic, Gene Expression Profiling, Hippocampus, Humans, Ion Channels, Mutation, Missense, Neurons, Polymorphism, Single Nucleotide, Risk Assessment
Abstract

Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well-characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders.

DOI10.1016/j.cell.2011.05.025
Alternate JournalCell
PubMed ID21703448
PubMed Central IDPMC3131217
Grant ListK08 NS047304 / NS / NINDS NIH HHS / United States
NS 049130 / NS / NINDS NIH HHS / United States
R01 NS049130 / NS / NINDS NIH HHS / United States
R01 NS049130-05 / NS / NINDS NIH HHS / United States