ArticleAnnals of neurology2020
SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.
Article in Annals of neurology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed, 93 citations in OpenAlex.
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- Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.Human molecular genetics · 2025Article
- Rare dysfunctional SCN2A variants are associated with malformation of cortical development.Epilepsia · 2025Article
- Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia.Nature communications · 2025Article
- Multiplexed CRISPRi Reveals a Transcriptional Switch Between KLF Activators and Repressors in the Maturing Neocortex.bioRxiv : the preprint server for biology · 2025Article
- Abnormality of Voltage-Gated Sodium Channels in Disease Development of the Nervous System. A Review Article.CNS & neurological disorders drug targets · 2025Review
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Authors and funding
36 authors at 20 institutions in 8 countries.
Funding
Abstract
objectivePathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.
methodsPatients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells).
resultsOf 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.
interpretationOur study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.
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