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Historically, BrS was believed to exhibit a Mendelian (autosomal dominant) mode of inheritance, caused by rare variants in\n                    <jats:italic>SCN5A<\/jats:italic>\n                    , the gene coding for the alpha subunit of the main cardiac sodium voltage channel. Challenges to this paradigm have arisen. For example, the majority of BrS cases do not exhibit rare variants in\n                    <jats:italic>SCN5A<\/jats:italic>\n                    . Moreover, genotype-phenotype mismatch in families has been observed. These findings suggest a more complex genetic architecture underpinning BrS. Subsequent large genomic studies of international patient cohorts have shown an unexpectedly high contribution of common genetic variation to its phenotypic development and severity. This has led to an alternative disease hypothesis whereby BrS develops as result of accumulated genetic and environmental risk surpassing a \u2018disease threshold\u2019 \u2013 the higher the accumulated risk, the more severe the clinical phenotype. Whilst expansion of standard clinical genetic testing to include an assessment of common variation might assist with diagnosis and phenotypic severity prediction in BrS, its incorporation into clinical practice presents inherent challenges which require careful consideration.\n                  <\/jats:p>","DOI":"10.1038\/s41431-025-01972-0","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T15:53:22Z","timestamp":1763135602000},"page":"904-913","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Brugada Syndrome: an exemplar for the genomic basis of sudden death"],"prefix":"10.1038","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5711-4039","authenticated-orcid":false,"given":"Rebecca L. 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