Abstract
BACKGROUND: Heterozygous SCN5A variants are associated with a wide spectrum of inherited arrhythmic disorders. However, little is known about the clinical phenotypes associated with biallelic (ie, homozygous or compound heterozygous) SCN5A variants. OBJECTIVE: The purpose of this study was to systematically review the clinical characteristics, outcomes, and genotype-phenotype correlations in patients with biallelic SCN5A variants. METHODS: We reviewed the available literature on patients with biallelic SCN5A variants and evaluated their demographic characteristics, medical history, and prognosis. RESULTS: A total of 33 articles were selected, comprising 61 patients from 43 families. Most were symptomatic at diagnosis (29/36, 81%), with common presentations including syncope (15/36, 42%) and cardiac arrest (10/36, 28%). Sinus node dysfunction was the most prevalent phenotype (35/54, 65%), often associated with atrial standstill (20/34, 59%). Other electrocardiographic abnormalities included progressive cardiac conduction disease (17/52, 33%), Brugada syndrome (12/52, 23%), overlap phenotypes (7/52, 13%), and long QT syndrome (2/52, 4%). During follow-up (median 5 ± 7 years), arrhythmias were common, and 76% (39/51) of patients required device implantation. Major cardiac events occurred in 50%, and 15% (8/55) died at a young age (mean 9 ± 15 years). Genotype analysis revealed 21 patients with homozygous SCN5A variants (34%) and 40 with compound heterozygous variants (66%). The type of variant, rather than zygosity, correlated with prognosis: a non-missense variant was associated with earlier onset and increased risk of major cardiac events. CONCLUSION: Patients with biallelic SCN5A variants display early-onset severe arrhythmic phenotypes with high morbidity and mortality. Improved recognition and international collaboration are essential to optimize diagnosis, management, and prevention of sudden cardiac death in this rare but high-risk population.