Rare variants and de novo variants in mesial temporal lobe epilepsy with hippocampal sclerosis

John K.L. Wong, Hongsheng Gui, Maxwell Kwok, Ping Wing Ng, Colin H.T. Lui, Larry Baum, Pak Chung Sham, Patrick Kwan, Stacey S. Cherny*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere245
JournalNeurology: Genetics
Volume4
Issue number3
DOIs
StatePublished - 1 Jun 2018

Funding

FundersFunder number
UCB Pharma
Eisai
Medical Research Institute Sri Lanka
Glaucoma Research Foundation
Chinese University of Hong Kong
General Research Fund of Shanghai Normal University
RGC General Research Fund GRF
RGC
Research Grants Council, University Grants Committee
University of Hong Kong
Bill and Melinda Gates Foundation
Universidade de Macau
National Natural Science Foundation of China
Not added1136427, 1103979
Hong Kong University Grants CouncilHKU 7630/ 12M
Australian Research CouncilDP140101967

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