SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families. (December 2020)

• Record Type: Journal Article
• Authors: Wijeyeratne, Yanushi D.; Tanck, Michael W.; Mizusawa, Yuka; Batchvarov, Velislav; Barc, Julien; Crotti, Lia; Bos, J. Martijn; Tester, David J.; Muir, Alison; Veltmann, Christian; Ohno, Seiko; Page, Stephen P.; Galvin, Joseph; Tadros, Rafik; Muggenthaler, Martina; Raju, Hariharan; Denjoy, Isabelle; Schott, Jean-Jacques; Gourraud, Jean-Baptiste; Skoric-Milosavljevic, Doris; Nannenberg, Eline A.; Redon, Richard; Papadakis, Michael; Kyndt, Florence; Dagradi, Federica; Castelletti, Silvia; Torchio, Margherita; Meitinger, Thomas; Lichtner, Peter; Ishikawa, Taisuke; Wilde, Arthur A.M.; Takahashi, Kazuhiro; Sharma, Sanjay; Roden, Dan M.; Borggrefe, Martin M.; McKeown, Pascal P.; Shimizu, Wataru; Horie, Minoru; Makita, Naomasa; Aiba, Takeshi; Ackerman, Michael J.; Schwartz, Peter J.; Probst, Vincent; Bezzina, Connie R.; Behr, Elijah R.;
• Is Part Of: Circulation. Volume 13:Number 6(2020)
• Publication Date: 2020-12
• Subjects: Brugada syndrome -- genetics, human -- penetrance -- phenotype -- risk score; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.120.002911
• Languages: English
• ISSNs: 2574-8300

Abstract

Abstract : 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. Abstract : Supplemental Digital Content is available in the text.