ArticleAmerican journal of human genetics2012
De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP.
Article in American journal of human genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 235 papers, 3 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
235 citing papers in PubMed, 3 syntheses or guidelines pooled it, 437 citations in OpenAlex.
- Bibliometric and visualized analysis of current advances and future directions in epilepsy: from molecular basis to therapy.Frontiers in neurology · 2025Pooled it
- Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.Pflugers Archiv : European journal of physiology · 2024Pooled it
- Do All Roads Lead to Rome? Genes Causing Dravet Syndrome and Dravet Syndrome-Like Phenotypes.Frontiers in neurology · 2022Pooled it
- Molecular mechanisms of sudden unexplained death and recent updates on molecular autopsy strategies for forensic investigation.International journal of legal medicine · 2026Review
- Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.Neural regeneration research · 2026Article
- Functional evidence for SCN8A splice-donor variant c.4419+1 A > G causing loss of function.Human genome variation · 2026Article
- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
- Nanoscale organization in the cell membrane dynamically modulates the biophysics of voltage-gated sodium channels.Nature communications · 2026Article
- Distinct neuronal mechanisms for motor impairment and seizures in a novel mouse model of SCN8A epileptic encephalopathy.Neurobiology of disease · 2026Article
- Base editing rescues seizures and sudden death in a SCN8A mutation-associated developmental epileptic encephalopathy model.The Journal of clinical investigation · 2026Article
- Neurologist's Black Swan: Molecular Basis of Prenatal Seizures.International journal of molecular sciences · 2025Review
- Article
- Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability.Cell reports · 2025Article
- Persistent Na+ current couples spreading depolarization to seizures in Scn8a gain-of-function mice.Brain : a journal of neurology · 2025Article
- A research roadmap for SCN8A-related disorders: addressing knowledge gaps and aligning research priorities across stakeholders.Orphanet journal of rare diseases · 2025Article
- Deciphering the Natural History ofNeurology · 2025Article
- Voltage-gated sodium channels in excitable cells as drug targets.Nature reviews. Drug discovery · 2025Review
- Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome.Translational psychiatry · 2025Review
- Abnormality of Voltage-Gated Sodium Channels in Disease Development of the Nervous System. A Review Article.CNS & neurological disorders drug targets · 2025Review
- Structural brain MRI abnormalities inFrontiers in neurology · 2025Article
175 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.