Abstract
Objective: Pathogenic 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. Methods: Patients 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). Results: Of 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. Interpretation: Our 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 348-362 |
| Number of pages | 15 |
| Journal | Annals of neurology |
| Volume | 88 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 1 2020 |
Funding
The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF\u20101009\u2010003), a parallel funding partnership between the Wellcome Trust, the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. This work was supported by NIH National Institute of Neurological Disorders and Stroke K08 NS097633, the Burroughs Wellcome Fund Career Award for Medical Scientists, and a March of Dimes Basil O'Connor Research Award to E.M.G.; and the Japan Agency for Medical Research and Development under the grant numbers JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, JP18kk020501, and Japan Society for the Promotion of Science KAKENHI under the grant numbers JP17K10080 to S.M. Authors K.S., A.E.J., E.P., B.B.\u2010Z., D.T.P., and A.E.F. are members of the European Network on Brain Malformations Neuro\u2010MIG European Cooperation in Science and Technology Action 16118. D.T.P. and A.E.F. were supported by the Newlife Foundation for Disabled Children (grant reference: 11\u201012/04), Wales Epilepsy Research Network, and Wales Gene Park. The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust, the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. This work was supported by NIH National Institute of Neurological Disorders and Stroke K08 NS097633, the Burroughs Wellcome Fund Career Award for Medical Scientists, and a March of Dimes Basil O'Connor Research Award to E.M.G.; and the Japan Agency for Medical Research and Development under the grant numbers JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, JP18kk020501, and Japan Society for the Promotion of Science KAKENHI under the grant numbers JP17K10080 to S.M. Authors K.S., A.E.J., E.P., B.B.-Z., D.T.P., and A.E.F. are members of the European Network on Brain Malformations Neuro-MIG European Cooperation in Science and Technology Action 16118. D.T.P. and A.E.F. were supported by the Newlife Foundation for Disabled Children (grant reference: 11-12/04), Wales Epilepsy Research Network, and Wales Gene Park. We thank X. Zhang for expert technical assistance; L. L. Isom for the gift of a ?-1 cDNA clone; and A. L. George for the gift of a ?-2 cDNA clone.
ASJC Scopus subject areas
- Neurology
- Clinical Neurology