Introduction
Brugada syndrome is a rare, potentially life-threatening genetic arrhythmia characterized by ST-segment elevations in leads (V1-V3) on the EKG and ventricular arrhythmias. It typically presents in adulthood but can be diagnosed at any age. The diagnosis is made clinically based on EKG findings. Molecular diagnosis can be confirmed with a pathogenic variant in the sodium channel SCN5A gene.  Loss-of-function variants in SCN5A are the most common cause found in 15-30% of cases. Brugada syndrome follows an autosomal dominant inheritance pattern, though affected individuals may show variable expressivity and reduced penetrance. 



This report introduces a novel Variant of Unknown Significance (VUS) in the SCN5A gene, underscoring the complexity of clinical decisions arising from uncertain genetic results.   

 

Case Presentation
A 34-year-old male with a personal and family history of Brugada syndrome presented for genetic testing. He was diagnosed at age 25 after an episode of syncope, preceded by palpitations, leading to ICD placement.  His family history is notable for the sudden cardiac death of his brother at age 21. It was unclear whether his brother’s EKG showed signs of Brugada pattern. The death certificate listed the cause of death as ventricular tachycardia, but post-mortem genetic testing was not performed.

Diagnostic Workup
Patient previously underwent genetic testing with the NGS Arrhythmia panel (25 genes). It identified a variant in SCN5A c.2893C>T, p.965R>C), which was believed to be the cause of his condition. but the report lacked patient identifiers preventing confirmation. Due to the lack of patient identifiers on the previous genetic test report and because the test was done nine years prior outside the United States, repeat testing was performed.



Results confirmed the presence of the SCN5A variant, predicted to be deleterious based on in silico analysis. This variant has been found in unrelated patients with Brugada syndrome, long QT syndrome, ARVC, and sudden unexplained death, but is also present in large population cohorts (gnomAD; internal data). The variant in SCN5A is highly suspicious and could be the cause of his phenotype; however, currently available data are insufficient to make a conclusive determination of the role of this variant in disease.   

Treatment and Management
Cascade testing was recommended for the patient's family. The patient's mother and sister were also found to carry the variant but have not experienced any cardiac events and are advised to undergo cardiac evaluation, including an EKG and a procainamide testing, which may help reveal Brugada syndrome. Fever management and the avoidance of drugs that could trigger arrythmia were discussed. 

Outcome and Follow-Up
The patient remains under the care of cardiology.. His genotype positive family members are currently undergoing clinical cardiac evalution. Due to the inconclusive results, genotype-negative family members were also encouraged to undergo clinical cardiac evaluation. A segregation study was considered, but not pursued as there are no other affected family members at this time. 

Discussion
In general, LQTS is associated with gain-of-function mutations in the SCN5A gene, (which encodes the NaV1.5 sodium channel), whereas Brugada syndrome is typically linked to loss-of-function variants. This variant has been found in individuals with different disease mechanisms and is present in the general population at a frequency higher than expected for pathogenic SCN5A variants, hence the supporting evidence remains inconclusive at this time. This report highlights a novel VUS in the SCN5A gene, emphasizing the challenges of variant interpretation and the difficulty of making clinical decisions based on uncertain genetic findings.

Conclusion
The VUS in SCN5A in this patient suggests potential pathogenicity. Management should include a combination of genetic testing, and clinical cardiac evaluation for family members, along with a segregation study.