Biallelic Truncating Variants in SCN3B Encoding Nav Channel Subunit β3 Lead to Neurodevelopmental Phenotype with and...

Area of Science:

• Neuroscience
• Genetics
• Channelopathies

Background:

• SCN3B encodes the beta-3 auxiliary subunit of voltage-gated sodium (Nav) channels, crucial for channel function.
• While linked to cardiac issues, SCN3B's role in neurodevelopmental disorders (NDD) was previously unestablished.

Purpose of the Study:

• To investigate the potential association between SCN3B mutations and NDD.
• To characterize the clinical and electrophysiological consequences of novel SCN3B variants.

Main Methods:

• Genotype-first approach in consanguineous Pakistani families.
• Identification and segregation analysis of homozygous truncating SCN3B variants.
• Electrophysiological studies on Nav channel subtypes.

Main Results:

• Identified homozygous truncating SCN3B variants (β3W94* and β3S196*) in two families.
• Affected individuals presented with global developmental delay, intellectual disability, autism, ataxia, and seizures.
• Electrophysiology revealed altered gating of multiple brain Nav channel subtypes.

Conclusions:

• This study establishes the first genetic link between SCN3B mutations and NDD.
• SCN3B variants contribute to a spectrum of neurodevelopmental phenotypes.
• Findings expand the understanding of Nav channelopathies and their impact on brain function.