Automated patch clamp data improve variant classification and
penetrance stratification for SCN5A–Brugada syndrome
Brugada Syndrome is a genetic condition that affects the heart’s electrical system. It is often diagnosed through electrocardiogram (ECG) testing and can lead to sudden cardiac death if untreated. Genetic changes (called variants) in the SCN5A gene affect heart function. This is because SCN5A gene makes the sodium channels (gates) that help regulate the heart’s electrical signals. When these signals are disrupted, it can lead to Brugada Syndrome. A key challenge in genetic testing is the uncertainty: many results come back as “variants of uncertain significance” (VUS), which creates a problem because it stays undetermined whether the genetic finding is causal to the disease. To help clear this up, this study focused on measuring how each genetic change in SCN5A gene impacts the heart’s sodium channel function. A total of 252 different SCN5Avariants or changes from Brugada syndrome patients were tested using a high-throughput method (test) that measures how well the heart’s sodium channel works. The study found the most harmful variants were mostly located in the central part of the heart’s sodium channel that allows sodium to enter the heart cells. Variants or changes in other regions of the channel generally worked normally, which means not all SCN5A variants are damaging, even if they come from Brugada syndrome patients. The study also shows that only the very rare changes tend to cause significant loss of function or impairment. Based on these findings, almost half of previously uncertain SCN5A variants could now be classified as “likely pathogenic (probably responsible).”
Besides genetic classification, this study also looked into the penetrance or the actuality of showing signs and symptoms, of Brugada syndrome, that is how likely you are to develop Brugada syndrome if you have a given variant. Only those variants that caused large decreases in channel function were linked to a high risk of developing Brugada Syndrome. So, it is not enough to know that a variant is present in SCN5A, knowing how much each variant affects the heart’s sodium channel function is important when managing Brugada syndrome patients.
O’Neill MJ, Ma JG, Aldridge JL, Solus JF, Harvey GR, Roberson PH, Barc J, Bezzina CR, Roden DM, Walsh R, Vandenberg JI, Glazer AM, Ng CA. Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.
Eur Heart J. 2025 Nov 18:ehaf874. doi: 10.1093/eurheartj/ehaf874. Epub ahead of print. PMID: 41251004.
Prepared by Andy Ng and Lorraine McGlinchey