ArticleHuman molecular genetics2014
Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 134 papers, 3 of them syntheses that pooled it.
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Who cites it
134 citing papers in PubMed, 3 syntheses or guidelines pooled it, 256 citations in OpenAlex.
- Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review.Frontiers in neurology · 2021Pooled it
- Intellectual Disability and Potassium Channelopathies: A Systematic Review.Frontiers in genetics · 2020Pooled it
- Genetic regulation of gene expression in the epileptic human hippocampus.Human molecular genetics · 2017Pooled it
- Factors affecting recall of different types of personal genetic information about Alzheimer's disease risk: the REVEAL study.Public health genomics · 2015Trial
- Unraveling the mechanisms of slack channel mutations in epileptic disorders.Acta epileptologica · 2026Review
- Expanding the phenotypic and genotypic spectrum ofBrain communications · 2026Article
- Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators.Science advances · 2025Article
- Electrophysiological characterization of human KCNT1 channel modulators and the therapeutic potential of hydroquinine and tipepidine in KCNT1 mutation-associated epilepsy mouse model.Acta pharmacologica Sinica · 2025Article
- Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool.Frontiers in genetics · 2025Article
- Structure-Activity Relationship Studies in a Series of 2-Aryloxy-Molecules (Basel, Switzerland) · 2024Article
- Broadening the scope of multigene panel analysis for adult epilepsy patients.Epilepsia open · 2024Article
- KCNT1 Channel Blockers: A Medicinal Chemistry Perspective.Molecules (Basel, Switzerland) · 2024Review
- Article
- Structure-Activity Relationship Studies in a Series of Xanthine Inhibitors of SLACK Potassium Channels.Molecules (Basel, Switzerland) · 2024Article
- Interaction Between HCN and Slack Channels Regulates mPFC Pyramidal Cell Excitability in Working Memory Circuits.Molecular neurobiology · 2024Article
- Targeted lipidomics analysis of possible molecular mechanisms of lipid changes in temporal lobe epilepsy models.Frontiers in pharmacology · 2024Article
- Design, synthesis, and biological evaluation of a novel series of 1,2,4-oxadiazole inhibitors of SLACK potassium channels: Identification of in vitro tool VU0935685.Bioorganic & medicinal chemistry · 2023Article
- Whole-Genome Sequencing Among Kazakhstani Children with Early-Onset Epilepsy Revealed New Gene Variants and Phenotypic Variability.Molecular neurobiology · 2023Article
- The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies.Molecular genetics & genomic medicine · 2023Article
- Genetic Testing in Children with Developmental and Epileptic Encephalopathies: A Review of Advances in Epilepsy Genomics.Children (Basel, Switzerland) · 2023Review
74 more citing papers are in PubMed but not listed here.
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Authors and funding
33 authors at 12 institutions in 5 countries.
Funding
Abstract
In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.
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