دورية أكاديمية
SCN5A Mutation Type and a Genetic Risk Score Associate Variably with Brugada Syndrome Phenotype in SCN5A Families.
| العنوان: | SCN5A Mutation Type and a Genetic Risk Score Associate Variably with Brugada Syndrome Phenotype in SCN5A Families. |
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| المؤلفون: | Wijeyeratne, YD, Tanck, MW, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, JM, Tester, DJ, Muir, A, Veltmann, C, Ohno, S, Page, SP, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J-J, Gourraud, J-B, Skoric-Milosavljevic, D, Nannenberg, EA, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, AAM, Takahashi, K, Sharma, S, Roden, DM, Borggrefe, MM, McKeown, PP, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, MJ, Schwartz, PJ, Probst, V, Bezzina, CR, Behr, ER |
| بيانات النشر: | American Heart Association |
| سنة النشر: | 2020 |
| المجموعة: | St George's University of London: Repository |
| الوصف: | 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 (SNP) 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 SNP risk alleles). Results - In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 4.15 for BrS phenotype (95%CI:1.45-11.85, p=0.0078). Amongst SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 2.35 (95%CI:0.89-6.22, p=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded and OR 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 OR=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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://openaccess.sgul.ac.uk/id/eprint/112608/1/CIRCGEN.120.002911.pdfTest; Wijeyeratne, YD; Tanck, MW; Mizusawa, Y; Batchvarov, V; Barc, J; Crotti, L; Bos, JM; Tester, DJ; Muir, A; Veltmann, C; et al. Wijeyeratne, YD; Tanck, MW; Mizusawa, Y; Batchvarov, V; Barc, J; Crotti, L; Bos, JM; Tester, DJ; Muir, A; Veltmann, C; Ohno, S; Page, SP; Galvin, J; Tadros, R; Muggenthaler, M; Raju, H; Denjoy, I; Schott, J-J; Gourraud, J-B; Skoric-Milosavljevic, D; Nannenberg, EA; Redon, R; Papadakis, M; Kyndt, F; Dagradi, F; Castelletti, S; Torchio, M; Meitinger, T; Lichtner, P; Ishikawa, T; Wilde, AAM; Takahashi, K; Sharma, S; Roden, DM; Borggrefe, MM; McKeown, PP; Shimizu, W; Horie, M; Makita, N; Aiba, T; Ackerman, MJ; Schwartz, PJ; Probst, V; Bezzina, CR; Behr, ER (2020) SCN5A Mutation Type and a Genetic Risk Score Associate Variably with Brugada Syndrome Phenotype in SCN5A Families. Circ Genom Precis Med, 13 (6). ISSN 2574-8300 https://doi.org/10.1161/CIRCGEN.120.002911Test SGUL Authors: Behr, Elijah Raphael Sharma, Sanjay |
| الإتاحة: | https://doi.org/10.1161/CIRCGEN.120.002911Test https://openaccess.sgul.ac.uk/id/eprint/112608Test/ https://openaccess.sgul.ac.uk/id/eprint/112608/1/CIRCGEN.120.002911.pdfTest |
| حقوق: | cc_by_4 |
| رقم الانضمام: | edsbas.7D7B1568 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |