ArticleJournal of medical genetics2015
De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy.
Article in Journal of medical genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
What it found
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Who cites it
78 citing papers in PubMed, 140 citations in OpenAlex.
- Molecular mechanisms of sudden unexplained death and recent updates on molecular autopsy strategies for forensic investigation.International journal of legal medicine · 2026Review
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- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
- Implication of genetic-dependent stage in the development ofFrontiers in human neuroscience · 2026Article
- Neurologist's Black Swan: Molecular Basis of Prenatal Seizures.International journal of molecular sciences · 2025Review
- FGF14 Peptide Derivative Differentially Regulates Nav1.2 and NaLife (Basel, Switzerland) · 2025Article
- PreMode predicts mode-of-action of missense variants by deep graph representation learning of protein sequence and structural context.Nature communications · 2025Article
- OCNDS core features are conserved across variants, with loop-region mutations driving greater symptom burden.Frontiers in human neuroscience · 2025Article
- Allele-Specific Editing of a Dominant SCN8A Epilepsy Variant Protects against Seizures and Lethality in a Murine Model.Annals of neurology · 2024Article
- Dentate gyrus granule cells are a locus of pathology in Scn8a developmental encephalopathy.Neurobiology of disease · 2024Article
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- Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Expanding the genotype-phenotype spectrum in SCN8A-related disorders.BMC neurology · 2024Article
- Biallelic structural variations withinLife science alliance · 2023Article
- Ataxia and Diplopia: A NewNeurology. Genetics · 2023Article
- A novelThe Journal of international medical research · 2023Article
- Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders.Life (Basel, Switzerland) · 2023Review
- Hominoid SVA-lncRNA AK057321 targets human-specific SVA retrotransposons in SCN8A and CDK5RAP2 to initiate neuronal maturation.Communications biology · 2023Article
- Detection of mosaic variants using genome sequencing in a large pediatric cohort.American journal of medical genetics. Part A · 2023Article
- Structure of human NaNature communications · 2023Article
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundMutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels.
methodsThe functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype-phenotype correlations of these and other cases were related to the functional analyses.
resultsThe first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel.
conclusionsComparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.
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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.