A novel SCN3B in-frame codon deletion in a Brugada syndrome patient: Implications for disrupted NaV1.5 function

Abstract

Introduction

Brugada Syndrome (BrS) is an inherited arrhythmia syndrome characterised by ST-segment elevation in the right precordial ECG leads and is associated with an increased risk of sudden cardiac death. We identify and characterise a novel SCN3B variant encoding the regulatory β3-subunit of the cardiac voltage-gated sodium channel, Na_V1.5.

Methods and results

A 54-year-old Caucasian male presented with palpitations and dizziness. An ECG identified a spontaneous type 1 BrS pattern and review of his medical records revealed a prior type 1 BrS ECG. Next generation sequencing of a BrS risk panel of genes identified a novel SCN3B deletion (c. c412–414, p.T138Del) yielding a single amino acid deletion. No other pathogenic variants were identified. Using site-directed mutagenesis we made the β3-ΔT138 variant and examined structural and functional effects in a heterologous system. Computational predictions together with circular dichroism spectroscopy showed highly localised structural perturbations with minimal effect on the gross protein architecture. Biotinylation, co-immunoprecipitation and surface cross-linking experiments identified normal β3 surface expression and interaction with Na_V1.5. Electrophysiological analysis identified reduced peak current and channel availability. Additionally, an accelerated fast inactivation was observed only in the presence of both wild-type and ΔT138 β3-subunits, reflecting the heterozygous individual. These effects are consistent with a loss-of-function phenotype.

Conclusion

A novel BrS associated SCN3B deletion introduced minimally disruptive structural perturbations to the regulatory β3-subunit of Na_V1.5, yet exerted significant electrophysiological effects. This variant highlights nuances of the Na_V1.5-β3 interaction and its role in maintaining normal cardiac excitability.