Key result
Comprehensive analysis of 133 rare variants in minor genes associated with Brugada syndrome identified only six variants in four genes with a conclusive pathogenic role.
Why the study?
Variants in 42 genes other than SCN5A have been reported as deleterious in Brugada syndrome, but have not received comprehensive pathogenic analysis.
Which minor genes beyond SCN5A have definitively pathogenic variants associated with Brugada syndrome?
Systematic Review
Which minor genes beyond SCN5A have definitively pathogenic variants associated with Brugada syndrome?
Beyond SCN5A, only four minor genes (SLMAP, SEMA3A, SCNN1A, and SCN2B) have definitively pathogenic variants associated with Brugada syndrome, highlighting the need for careful clinical translation of genetic findings.
Answers are grounded in this paper and cite their sources.
Most minor-gene variants lack conclusive pathogenicity; leaves open definitive roles for remaining candidates pending validation.
Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.
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Campuzano et al. (2019) conducted a systematic review in Brugada syndrome. Genetic interpretation of minor genes was evaluated on Pathogenicity of rare variants associated with Brugada syndrome. Comprehensive analysis of 133 rare variants in minor genes associated with Brugada syndrome identified only six variants in four genes with a conclusive pathogenic role.
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