Dominant negative effects of SCN5A missense variants

Purpose: Up to 30% of patients with Brugada syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A encoding for the protein Na(V)1.5. Recent studies suggested that Na(V)1.5 can dimerize, and some variants exert dominant negative effects. In this study, we sought to explore the generality of missense variant Na(V)1.5 dominant negative effects and their clinical severity. Methods: We identified 35 LoF variants (<10% of wild type [WT] peak current) and 15 partial LoF variants (10%-50% of WT peak current) that we assessed for dominant negative effects. SCN5A variants were studied in HEK293T cells, alone or in heterozygous coexpression with WT SCN5A using automated patch clamp. To assess the clinical risk, we compared the prevalence of dominant negative vs putative haploinsufficient (frameshift, splice, or nonsense) variants in a BrS consortium and the Genome Aggregation Database population database. Results: In heterozygous expression with WT, 32 of 35 LoF and 6 of 15 partial LoF variants showed reduction to <75% of WT-alone peak current, showing a dominant negative effect. Individuals with dominant negative LoF variants had an elevated disease burden compared with the individuals with putative haploinsufficient variants (2.7-fold enrichment in BrS cases, P = .019). Conclusion: Most SCN5A missense LoF variants exert a dominant negative effect. This class of variant confers an especially high burden of BrS. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

This study aimed to investigate the dominant negative effects and clinical severity of loss-of-function variants in the cardiac sodium channel gene in patients with Brugada syndrome. The results showed that most loss-of-function variants exert dominant negative effects and are associated with an increased disease burden in Brugada syndrome.