Abstract Body: Background: Sick sinus syndrome (SSS) is a cardiac condition caused by sinoatrial node dysfunction, leading to arrhythmias due to the inability to transmit signals properly to the upper chambers of the heart. While age-related degeneration of the sinoatrial node is the most common contributing factor to SSS, congenital disorders involving genetic variants can also lead to its development, even in pediatric patients. To explore the genetic basis of SSS in the pediatric population (age < 19 years), we conducted a comprehensive review of case reports to identify associated genetic variants. Our focus centered on variants reported in the sodium channel protein type 5 subunit alpha (SCN5A) gene, which has been reported to contribute to various ventricular arrhythmias, including SSS.
Methods: A comprehensive literature review of case reports of juvenile-onset SSS was conducted using PubTator/PubMed and the Online Mendelian Inheritance in Man (OMIM) database to identify SCN5A variants. Case reports were selected if they met the following criteria: at least one patient diagnosed with SSS at or under the age of 19 with a detected variant in the SCN5A gene. The structural effects of identified variants were assessed using the HOPE web service.
Results: Data compiled from the literature review provided a total of 53 cases related to juvenile-onset SSS and the SCN5A gene. Among the reported patients, many exhibited multiple arrhythmogenic phenotypes alongside SSS, including progressive cardiac conduction disease, idiopathic ventricular tachycardia, and Brugada syndrome. The majority of identified variants were missense, although truncating and insertion/deletion variants were also documented. All three inheritance variations - heterozygous, homozygous, and compound heterozygous - were observed in this set of patients. Although many of the variants had some functional studies performed to determine their pathogenicity, some of the variants did not have a predicted impact. For these variants, we characterized the location and biochemical properties of the variants, comparing them to the variants with known functional impact.
Conclusion: Future studies will explore the functional impact associated with the predicted variants through modeling specific mutations in SCN5A, using cardiomyocytes in vitro. Additionally, using further published studies and surveying the protein structure analysis of SCN5A variants will aid in characterizing those that are specific to SSS.