RT Journal Article
SR Electronic
T1 Rare variants and de novo variants in mesial temporal lobe epilepsy with hippocampal sclerosis
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e245
DO 10.1212/NXG.0000000000000245
VO 4
IS 3
A1 Wong, John K.L.
A1 Gui, Hongsheng
A1 Kwok, Maxwell
A1 Ng, Ping Wing
A1 Lui, Colin H.T.
A1 Baum, Larry
A1 Sham, Pak Chung
A1 Kwan, Patrick
A1 Cherny, Stacey S.
YR 2018
UL http://ng.neurology.org/content/4/3/e245.abstract
AB Objective We investigated the role of rare genetic variants and of de novo variants in the pathogenesis of mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS).Methods Whole-exome sequencing (WES) was performed in patients with MTLE-HS and their unaffected parents (trios). Genes or gene sets that were enriched with predicted damaging rare variants in the patients as compared to population controls were identified. Patients and their parents were compared to identify whether the variants were de novo or inherited.Results After quality control, WES data from 47 patients (26 female), including 23 complete trios, were available for analysis. Compared with population controls, significant enrichment of rare variants was observed in SEC24B. Integration of gene set data describing neuronal functions and psychiatric disorders showed enrichment signal on fragile X mental retardation protein (FMRP) targets. Twenty-one de novo variants were identified, with many known to cause neuropsychiatric disorders. The FMRP-targeted genes also carried more de novo variants. Inherited compound heterozygous and homozygous variants were identified.Conclusions The genetic architecture underlying MTHE-HS is complex. Multiple genes carrying de novo variants and rare variants among FMRP targets were identified, suggesting a pathogenic role. MTLE-HS and other neuropsychiatric disorders may have shared biology.ASD=autism spectrum disorder; ExAC=Exome Aggregation Consortium; FMRP=fragile X mental retardation protein; GWAS=genome-wide association study; HS=hippocampal sclerosis; IL=interleukin; MAF=minor allele frequency; MGI=Mouse Genome Informatics; mGluR=metabotropic glutamate receptor; MTLE-HS=mesial temporal lobe epilepsy related to hippocampal sclerosis; NMDAR=NMDA receptor; SNP=single nucleotide polymorphism; WES=whole-exome sequencing