Scn5a mutation type and a genetic risk score associate variably with brugada syndrome phenotype in scn5a families

Yanushi D. Wijeyeratne, Michael W. Tanck, Yuka Mizusawa, Velislav Batchvarov, Julien Barc, Lia Crotti, J. Martijn Bos, David J. Tester, Alison Muir, Christian Veltmann, Seiko Ohno, Stephen P. Page, Joseph Galvin, Rafik Tadros, Martina Muggenthaler, Hariharan Raju, Isabelle Denjoy, Jean-Jacques Schott, Jean-Baptiste Gourraud, Doris Skoric-MilosavljevicEline A. Nannenberg, Richard Redon, Michael Papadakis, Florence Kyndt, Federica Dagradi, Silvia Castelletti, Margherita Torchio, Thomas Meitinger, Peter Lichtner, Taisuke Ishikawa, Arthur A. M. Wilde, Kazuhiro Takahashi, Sanjay Sharma, Dan M. Roden, Martin M. Borggrefe, Pascal P. McKeown, Wataru Shimizu, Minoru Horie, Naomasa Makita, Takeshi Aiba, Michael J. Ackerman, Peter J. Schwartz, Vincent Probst, Connie R. Bezzina, Elijah R. Behr

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39 Citations (Scopus)


Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.
Original languageEnglish
Article number002911
Pages (from-to)599-608
Number of pages10
JournalCirculation: Genomic and Precision Medicine
Early online date2020
Publication statusPublished - 2020


  • Brugada syndrome
  • genetics, human
  • penetrance
  • phenotype
  • risk score

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