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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)
Postprint Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Brugada Syndrome ; Genetics, Human ; Penetrance ; Phenotype ; Risk Score
ISSN (print) / ISBN 2574-8300
e-ISSN 2574-8300
Journal Circulation Genomic and precision medicine
Quellenangaben Volume: 13, Issue: 6, Pages: 599-608 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Philadelphia, Pa.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Grants Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program
National Institute of Health Research
Higher Education Funding Council for England
British Heart Foundation (BHF)
BHF Project Grant
BHF Clinical Research Training Fellowship
Medical Research Council
Dutch Heart Foundation
Netherlands Organization for Scientific Research (VICI Fellowship)
Philippa and Marvin Carsley Cardiology Chair
James Lancaster Memorial Fund - McColl's RG Ltd.