Reaffirmation Of Gpd1l-A280v As A Brugada Syndrome Disease-Causing Variant

Introduction: Brugada Syndrome (BrS) is an inherited arrhythmia syndrome characterized by ST-segment elevation in the right precordial leads (V1-V3) and sudden cardiac death; ~20% of cases are caused by mutations in SCN5A . Over the past two decades, over 20 genes that may cause BrS have been identified. We reported that a Glycerol-3-Phosphate Dehydrogenase 1-Like mutation (GPD1L;p.A280V, chromosome 3p22.3) was linked to BrS in a large, multigenerational family with a LOD score ~4. Recent efforts in the field have called into question the pathogenicity of non- SCN5A genetic variants in BrS. Hypothesis: We sought to confirm the role of GPD1L in this family using a high density SNP array to narrow the linkage region and whole exome sequencing (WES) of the proband to rule out other possible mutations. We also sought to test whether BrS susceptibility SNPs in SCN5A and SCN10A linked to GPD1L may play a role in this family. Methods: SNPs were identified on an Illumina Global Screening Array and used for fine mapping. The exome of the proband was captured with the Agilent V6+UTR kit. SNPs were called using GATK3. BrS susceptibility SNPs were confirmed by PCR amplification and Sanger Sequencing. Results: The linkage region in this family resolved to ~3.07 MB (hg19; 3:29,899,567-32,970,637; Figure). This region contained 14 genes including GPD1L , and lacking SCN5A , SCN10A , or any other BrS-associated gene. WES identified GPD1L;p.A280V as the only coding variant in the linkage region with an allele frequency ≤ 1%. Previously identified BrS risk alleles in SCN5A and SCN10A were linked to the GPD1L;p.A280V allele in most family members (Figure). Conclusions: Our data suggests that GPD1L;p.A280V causes BrS in this family. The pathogenicity of GPD1L;p.A280V may be increased by linkage with SCN5A and SCN10A risk SNPs. The role of GPD1L mutations in the pathogenesis of BrS should be reaffirmed.