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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by R01HL062300, R01HL077398, and R01HL115955. Mr. Greiner is also supported by an NIH Ruth L. Kirschstein F30 fellowship (F30HL143908) and by a T32 training grant held by the University of Iowa Medical Scientist Training Program (T32GM007337). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Pittsburgh Institutional Review Board and University of Iowa Institutional Review Board I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * BrS : Brugada Syndrome SNP : Single nucleotide polymorphism CM : centimorgan LOD : logarithm of the odds Mb : megabase ICD : implantable cardioverter defibrillator RBBB : right bundle branch block VT : ventricular tachycardia