SCN3A-related neurodevelopmental disorder: Clinical case reports and biophysical characterization.

Abstract

SCN3A, the gene encoding the voltage-gated sodium channel, Nav1.3, plays a critical role in early neuronal development. Although traditionally considered a neonatal channel, emerging evidence has linked SCN3A mutations to a spectrum of neurodevelopmental disorders. Here, we report two clinical cases involving rare SCN3A variants: one with a de novo p.L209P mutation and another with compound heterozygous p.N52H and p.E1809K variants. Whole-exome sequencing and clinical phenotyping revealed overlapping features of global developmental delay, hypotonia, structural brain abnormalities, and, in one case, epilepsy and dystonia. To evaluate their functional impact, we expressed each mutant independently in CHO cells co-transfected with β1 subunits and performed whole-cell patch-clamp electrophysiology. p.N52H reduced current density and hyperpolarized activation, suggesting mixed gain- and loss-of-function effects. p.L209P selectively hyperpolarized the activation curve, while p.E1809K altered fast inactivation and accelerated recovery kinetics. These findings demonstrate that SCN3A variants can disrupt excitability through diverse biophysical mechanisms. Our study expands the clinical and functional landscape of SCN3A-related disorders and underscores the importance of variant-level characterization to guide diagnosis and future therapeutic strategies.