Citations 1
SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families
Wijeyeratne, Yanushi D. , Tanck, Michael W.T. , Mizusawa, Yuka , Batchvarov, Velislav N., Barc, Julien , Crotti, Lia , Bos, J. Martijn , Tester, David J. , Muir, Alison , Veltmann, Christian , Ohno, Seiko , Page, Stephen P, Galvin, Joseph , Muggenthaler, Martina, Gourraud, Jean‐Baptiste , Škorić‐Milosavljević, Doris , Nannenberg, Eline A., Redon, Richard , Castelletti, Silvia , Torchio, Margherita , Lichtner, Peter , Wilde, Arthur A.M. , Takahashi, Kazuhiro , Sharma, Sanjay , Roden, Dan M. , Borggrefe, Martin , McKeown, Pascal , Horie, Minoru , Makita, Naomasa , Aiba, Takeshi , Ackerman, Michael J. , Bezzina, Connie R. , Behr, Elijah R. , Crotti, Lia , Makita, Naomasa , Horie, Minoru , Behr, Elijah Raphael , Sharma, Sanjay , Bos, Johan M , Tanck, Michael , Barc, Julien , Redon, Richard , Bezzina, Connie R , Gourraud, Jean-Baptiste , Veltmann, Christian , Ohno, Seiko , Tadros, Rafik , Raju, Hariharan , Denjoy, Isabelle , Schott, Jean‐Jacques , Papadakis, Michael , Kyndt, Florence , Dagradi, Federica , Meitinger, Thomas , Ishikawa, Taisuke , Roden, Dan M. , Shimizu, Wataru , Aiba, Takeshi , Schwartz, Peter J. , Probst, Vincent
Circulation: Genomic and Precision Medicine | November 9, 2020 | Volume: 13 | Issue: 6 | Pages: No page available
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.