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Updated: Apr 6, 2026
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
High-throughput genetic characterization of a cohort of Brugada syndrome patients
Chiara Di Resta1, Alessandro Pietrelli2, Simone Sala3
1Vita-Salute San Raffaele University, Milan, Italy.
Insights
Brugada syndrome (BrS) genetic diagnosis remains challenging, as most mutations are in SCN5A. This study identified new candidate genes, DSG2 and MYH7, expanding understanding of BrS genetic heterogeneity.
Area of Science:
- Cardiovascular Genetics
- Inherited Arrhythmia Syndromes
- Sudden Cardiac Death Etiologies
Background:
- Brugada syndrome (BrS) is an inherited cardiac disorder causing sudden death, primarily affecting males. Genetic underdiagnosis is high, with SCN5A mutations identified in fewer than 30% of patients.
- While SCN5A is the main gene implicated, over 21 other genes are linked to BrS susceptibility, yet their roles remain largely unknown.
- Previous studies using next-generation sequencing found significant enrichment only for SCN5A, highlighting the need for broader genetic investigations.
Purpose of the Study:
- To investigate the genetic basis of Brugada syndrome in a cohort of SCN5A-negative patients.
- To identify novel candidate genes contributing to BrS pathogenesis beyond SCN5A.
- To explore potential genetic overlap between Brugada syndrome and other cardiac channelopathies.
Main Methods:
- Evaluated functional variants in 158 arrhythmia-associated genes in 91 SCN5A-negative BrS patients.
- Utilized a mutation burden test comparing BrS patients to European controls from the 1000 Genomes project.
- Employed next-generation sequencing for comprehensive genetic analysis.
Main Results:
- Confirmed the genetic heterogeneity of Brugada syndrome.
- Identified DSG2 and MYH7 as potential novel candidate genes for BrS.
- Observed a significant enrichment of variants in SCN5A in previous studies, but this study focused on SCN5A-negative cases.
Conclusions:
- The genetic landscape of Brugada syndrome is complex, involving multiple genes beyond SCN5A.
- DSG2 and MYH7 represent promising new targets for genetic testing in SCN5A-negative BrS patients.
- Findings suggest a potential genetic overlap between Brugada syndrome and other cardiac disorders, warranting further research.
Abstract:
Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder that can lead to sudden death, with a prevalence of 1:5000 in Caucasian population and affecting mainly male patients in their third to fourth decade of life. BrS is inherited as an autosomal dominant trait; however, to date genetic bases have been only partially understood. Indeed most mutations are located in the SCN5A gene, encoding the alpha-subunit of the Na(+) cardiac channel, but >70% BrS patients still remain genetically undiagnosed. Although 21 other genes have been associated with BrS susceptibility, their pathogenic role is still unclear. A recent next-generation sequencing study investigated the contribution of 45 arrhythmia susceptibility genes in BrS pathogenesis, observing a significant enrichment only for SCN5A. In our study, we evaluated the distribution of putative functional variants in a wider panel of 158 genes previously associated with arrhythmic and cardiac defects in a cohort of 91 SCN5A-negative BrS patients. In addition, to identify genes significantly enriched in BrS, we performed a mutation burden test by using as control dataset European individuals selected from the 1000Genomes project. We confirmed BrS genetic heterogeneity and identified new potential BrS candidates such as DSG2 and MYH7, suggesting a possible genetic overlap between different cardiac disorders.
