PuSH - Publication Server of Helmholtz Zentrum München: <em>Scn5a</em> mutation type and a genetic risk score associate variably with brugada syndrome phenotype in<em> scn5a</em> families.

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Wijeyeratne, Y.D.* ; Tanck, M.W.* ; Mizusawa, Y.* ; Batchvarov, V.* ; Barc, J.* ; Crotti, L.* ; Bos, J.M.* ; Tester, D.J.* ; Muir, A.M.* ; Veltmann, C.* ; Ohno, S.* ; Page, S.P.* ; Galvin, J.* ; Tadros, R.* ; Muggenthaler, M.* ; Raju, H.* ; Denjoy, I.* ; Schott, J.J.* ; Gourraud, J.B.* ; Skoric-Milosavljevic, D.* ; Nannenberg, E.A.* ; Redon, R.* ; Papadakis, M.* ; Kyndt, F.* ; Dagradi, F.* ; Castelletti, S.* ; Torchio, M.* ; Meitinger, T. ; Lichtner, P. ; Ishikawa, T.* ; Wilde, A.A.M.* ; Takahashi, K.* ; Sharma, S.* ; Roden, D.M.* ; Borggrefe, M.M.* ; McKeown, P.P.* ; Shimizu, W.* ; Horie, M.* ; Makita, N.* ; Aiba, T.* ; Ackerman, M.J.* ; Schwartz, P.J.* ; Probst, V.* ; Bezzina, C.R.* ; Behr, E.R.*

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

Circ. Genom. Precis. Med. 13, 599-608 (2020)

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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.

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