What is the risk of dangerous arrhythmias in SCN5A loss-of-function mutation carriers?

The SCN5A gene (cardiac sodium channel gene), is important for the transmission of electrical signals throughout the heart and therefore important for maintaining a normal heart rhythm. In case of a disease causing loss-of-function change (an error in the DNA leading to a less working sodium channel) in this SCN5A gene, non-functional sodium channels will be produced, which can lead to transmission disorders and potentially deadly arrhythmias (coming from the lower heart chambers). Diseases that could possibly be caused by these mutations are amongst others Brugada syndrome (BrS) and progressive cardiac conduction disorder (PCCD). BrS and PCCD are rare cardiac rhythm disorders with either a high risk of dangerous arrhythmias leading to death (BrS) or extreme slowing of the transmission system of the heart that can result in a complete heart block (PCCD). Interestingly, not every patient with such a mutation will develop these diseases and if they do they are not always seriously affected. In fact, many patients carrying such a mutation will not develop dangerous arrhythmias or a complete heart block at all and stay asymptomatic throughout their life. One of the difficulties is that we do not know what is causing patients to become either symptomatic or asymptomatic (showing symptoms or not), especially because this can even differ between family members carrying the same alteration. In this study we investigated how many patients developed dangerous arrhythmias during follow-up and to find features that can predict if someone is going to develop dangerous arrhythmias.

Data of patients with an SCN5A loss-of-function mutation from two hospitals, Nantes and Amsterdam were collected from the already existing patient files. We collected baseline characteristics (sex, age, genetics, symptoms) and if dangerous arrhythmias occurred during the years after they were first seen by a cardiologist. Patients that had a history of arrhythmias were categorized as ‘symptomatic’.

We included 615 patients with a loss-of-function SCN5A mutation. Within a median time period of 9,5 years (5.0-14.3), 6.7% of the patients had a dangerous arrhythmia. The number of patients with a dangerous arrhythmia was higher in the ‘symptomatic’ group (23.4%) compared to the asymptomatic group (3.0%). We found that being symptomatic at baseline, the male sex and QRS prolongation were predictors for the occurrence of dangerous arrhythmias. It seems that particularly the women with a normal QRS duration were at low risk for dangerous arrhythmias. We think that these findings could benefit to a more individual approach.

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Tuijnenburg F, Proost VM, Thollet A, Barc J, Groffen AJA, Veerman CC, van der Crabben SN, van der Pas VR, Kyndt F, Jurgens SJ, Tanck MWT, Postema PG, van Tintelen JP, Bezzina CR, Probst V, Wilde AAM, Gourraud JB, Amin AS. Long-term prognosis of patients with an SCN5A loss-of-function variant and progressive cardiac conduction disorder or Brugada syndrome.
Heart Rhythm. 2024 Nov 2:S1547-5271(24)03518-5. doi: 10.1016/j.hrthm.2024.10.057. Online ahead of print. PMID: 39491571

Prepared by Fenna Tuijenburg and Lorraine McGlinchey