Biallelic Truncating Variants in SCN3B Encoding Nav Channel Subunit β3 Lead to Neurodevelopmental Phenotype with and without Epilepsy and Ataxia

SCN3B encodes the β3 auxiliary subunit, essential for voltage‐gated Na + (Nav) channel trafficking and gating. Although SCN3B has been associated with cardiac disorders, a link with neurodevelopmental disorders (NDD) has not been established. Using a genotype‐first approach, we identified homozygous truncating variants (c.281G>A‐β3 W94* , c.584 + 1G>A‐β3 S196* ) in 2 consanguineous Pakistani families, leading to global developmental delay, intellectual disability and autism, with severe cognitive impairment, ataxia, and seizures in the case of β3 W94* . Electrophysiological analysis revealed subtype‐specific gating alterations on multiple brain Nav channel subtypes. This is the first report linking SCN3B mutations to NDD, expanding our understanding of Nav channelopathies. ANN NEUROL 2025