Brugada Syndrome (BrS) is an inherited arrhythmia syndrome in which mutations in the cardiac sodium channel
We sought to re-assess the genetic underpinnings of BrS in a large mutligenerational family with a putative mutation in
Fine linkage mapping was performed in the family using the Illumina Global Screening Array. Whole exome sequencing of the proband was performed to identify rare variants and mutations, and Sanger sequencing was used to assay previously-reported risk single nucleotide polymorphsims (SNPs) for BrS.
Linkage analysis decreased the size of the previously-reported microsatellite linkage region to approximately 3 Mb. GPD1L-A280V was the only coding non-synonymous variation present at less than 1% allele frequency in the proband within the linkage region. No rare non-synonymous variants were present outside the linkage area in affected individuals in genes associated with BrS. Risk SNPs known to predispose to BrS were overrepresented in affected members of the family.
Together, our data suggest GPD1L-A280V remains the most likely cause of BrS in this large multigenerational family. While care should be taken in interpreting variant pathogenicity given the genetic uncertainty of BrS, our data support inclusion of other putative BrS genes in clinical genetic panels.