title: High-throughput genetic characterization of a cohort of Brugada syndrome patients.
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.
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Di Resta
authors.affiliation: Institute of Biomedical Technologies, National Research Council of Italy (ITB-CNR), Milan, Italy, Molecular Medicine, University of Milan, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pietrelli
authors.affiliation: Department of Arrhythmology.
authors.forename: Simone
authors.initials: S
authors.lastname: Sala
authors.affiliation: Department of Arrhythmology.
authors.forename: Paolo
authors.initials: P
authors.lastname: Della Bella
authors.affiliation: Institute of Biomedical Technologies, National Research Council of Italy (ITB-CNR), Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: De Bellis
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy, Laboratory of Clinical Molecular Biology and Cytogenetics and Genomic Unit for the Diagnosis of Human Pathologies, Division of Genetics and Cellular Biology, IRCCS San Raffaele Hospital, Milan, Italy ferrari.maurizio@hsr.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Institute of Biomedical Technologies, National Research Council of Italy (ITB-CNR), Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bordoni
authors.affiliation: Laboratory of Clinical Molecular Biology and Cytogenetics and.
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
mesh_terms: D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism; D024722:Cardiac Myosins / Q000235:genetics; D004252:DNA Mutational Analysis; D051301:Desmoglein 2 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C495314:DSG2 protein, human; D051301:Desmoglein 2; C501641:MYH7 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains