SCN3A-related neurodevelopmental disorder: Clinical case reports and biophysical characterization
Mohammad-Reza Ghovanloo1,2, Cynthia Gershome1, Robin van der Lee3
1Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
Channels (Austin, Tex.)
|October 30, 2025
Summary
Rare SCN3A gene variants are linked to neurodevelopmental disorders. These mutations in the Nav1.3 sodium channel disrupt neuronal function through various mechanisms, impacting early brain development.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The SCN3A gene encodes the Nav1.3 sodium channel, crucial for early neuronal development.
- Mutations in SCN3A are increasingly associated with a range of neurodevelopmental disorders.
Purpose of the Study:
- To investigate the clinical and functional impact of rare SCN3A variants in two patients.
- To characterize the biophysical mechanisms underlying SCN3A-related neurodevelopmental phenotypes.
Main Methods:
- Whole-exome sequencing and clinical phenotyping of patients with SCN3A variants.
- Functional characterization of SCN3A variants using whole-cell patch-clamp electrophysiology in CHO cells.
Main Results:
- Two patients presented with global developmental delay, hypotonia, and brain abnormalities, associated with SCN3A variants.
- p.N52H variant showed reduced current density and altered activation; p.L209P hyperpolarized activation; p.E1809K affected inactivation and recovery.
- These variants disrupt neuronal excitability through distinct biophysical mechanisms.
Conclusions:
- SCN3A variants contribute to neurodevelopmental disorders via diverse functional disruptions.
- Detailed variant characterization is essential for accurate diagnosis and therapeutic development in SCN3A-related conditions.
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