Dominant negative effects of SCN5A missense variants
Preprint
Abstract
Introduction: Up to 30% of patients with Brugada Syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A . Recent studies have suggested that the SCN5A protein product Na V 1.5 can form dimers and exert dominant negative effects. Methods: We identified 35 LoF variants (SCN5A variants were studied in HEK293T cells alone or in heterozygous co-expression with WT SCN5A using automated patch clamp. To assess clinical risk, we compared the prevalence of dominant negative vs. putative haploinsufficient (frameshift/splice site) variants in a BrS case consortium and the gnomAD population database. Results: In heterozygous expression with WT, 32/35 LoF variants and 6/15 partial LoF showed reduction to Na , demonstrating a dominant negative effect. Carriers of dominant negative LoF missense variants had an enriched disease burden compared to putative haploinsufficient variant carriers (2.7-fold enrichment in BrS cases, p=0.019). Conclusions: Most SCN5A missense LoF variants exert a dominant negative effect. Cohort analyses reveal that this class of variant confers an especially high burden of BrS.Keywords
All Related Versions
- Published version: Genetics in Medicine, 24 (6), 1238.
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