Additional Evidence Implicating GPD1L in the Pathogenesis of Brugada Syndrome in A Large Multi-generational Family

Background Brugada Syndrome (BrS) is an inherited arrhythmia syndrome in which mutations in SCN5A account for 20% of cases. Mutations in other ion channels or channel-modifying genes may account for an additional 10% of cases, though recent analysis has suggested that SCN5A should be regarded as the sole monogenic cause of BrS. Objective We sought to re-assess the genetic underpinnings of BrS in a large mutligenerational family with a putative GPD1L-A280V mutation. Methods 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. Results Linkage analysis decreased the size of the previously-reported microsatellite linkage region to ∼3 megabases. GPD1L-A280V was the only rare coding non-synonymous variation present at < 1% allele frequency in the proband within the linkage region. Other variants were either synonymous, or in genes not known to play a role in BrS and that failed to co-segregate with BrS in the large family. Risk SNPs known to predispose to BrS were overrepresented in affected members of the family. Conclusion Together, our linkage and sequencing data suggest GPD1L-A280V remains the most likely cause of BrS in this large mutligenerational family. While care should be taken in interpreting variant pathogenicity given the genetic uncertainty of BrS, our data support inclusion of other putative BrS in clinical genetic panels.