Author + information
- Shengchuan Daia,b,
- Haider Mehdia,b,
- Gina Morgana,b,
- Rebecca Gutmanna,b,
- Alexander Greinera,b,
- Anthony Klappaa,b,
- Jeanne Nerbonnea,b and
- Barry Londona,b
Background: Mutations in the voltage-gated sodium channel (SCN5A; Nav1.5) and its regulating genes, such as fibroblast growth factor 12 (FGF12), are linked to Brugada syndrome (BrS). The goal of this study is to identify additional FGF12 mutations and variants that may be linked to BrS.
Methods: Twenty-five BrS probands were sequenced for near promoter, intron-exon boundaries, and exons of FGF12. One of the probands carrying the FGF12 variation was sent for genetic testing (GeneDx).
Results: We identified a rare splice-site mutation in intron 7 of SCN5A (c.934+1G>A) and a TT insertion variant in intron 3 of FGF12 (−6insTT, rs199817584) near the splice acceptor site for exon 4. All individuals carrying both the SCN5A c.934+1G>A mutation and the FGF12 −6insTT variation were clinically affected with BrS, while those with either the mutation or variation were unaffected (Figure 1). We also found that the FGF12 −6insTT variation altered splicing efficiency, leading to skipping of Exon 4 and reduced gene expression. Two additional FGF12 SNPs (rs75996617 and rs79006332) in intron 3 were linked to −6insTT.
Conclusions: Both a loss-of-function SCN5A mutation (c.934+1G>A) and a FGF12 variant (−6insTT) causes BrS in a multigenerational family. These findings provide further evidence for the role of Na+ channel modifiers in modulating the penetrance of BrS.
Moderated Poster Contributions
Arrhythmias and Clinical EP Moderated Poster Theater, Poster Hall, Hall C
Saturday, March 18, 2017, 4:15 p.m.-4:25 p.m.
Session Title: Cardiac Channelopathies: Novel Therapeutics and Clinical Challenges
Abstract Category: 4. Arrhythmias and Clinical EP: Basic
Presentation Number: 1262M-07
- 2017 American College of Cardiology Foundation