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

Autor:	Wijeyeratne YD; Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.)., Tanck MW; Departments of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health (M.W.T.)., Mizusawa Y; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC (Y.M., R.T., D.S.-M., E.A.N., A.A.M.W., C.R.B.), University of Amsterdam, the Netherlands., Batchvarov V; Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.)., Barc J; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; l'institut du thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., R.R., F.K.)., Crotti L; Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics (L.C., F.D., S.C., M.T., P.J.S.), Milan, Italy.; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Istituto Auxologico Italiano, IRCCS, Milan, Italy (L.C.)., Bos JM; Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (J.M.B., D.J.T., M.J.A.)., Tester DJ; Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (J.M.B., D.J.T., M.J.A.)., Muir A; Belfast Health & Social Care Trust, United Kingdom (A.M., P.P.M.)., Veltmann C; Rhythmology and Electrophysiology, Department of Cardiology and Angiology, Hannover Medical School, Germany (C.V.)., Ohno S; Shiga University of Medical Science (S.O., M.H.).; National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.)., Page SP; Leeds Teaching Hospitals NHS Trust, United Kingdom (S.P.P.)., Galvin J; Mater University and Private Hospitals, Dublin, Ireland (J.G.)., Tadros R; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC (Y.M., R.T., D.S.-M., E.A.N., A.A.M.W., C.R.B.), University of Amsterdam, the Netherlands., Muggenthaler M; Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.)., Raju H; Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.)., Denjoy I; AP-HP, Hôpital Bichat, Dépt de Cardiologie et Ctr de Référence des Maladies Cardiaques Héréditaires, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France INSERM U1166 (I.D.)., Schott JJ; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; l'institut du thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., R.R., F.K.).; CHU Nantes, Service de Génétique Médicale (J.-J.S., J.-B.G., R.R.)., Gourraud JB; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; l'institut du thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., R.R., F.K.).; CHU Nantes, Service de Génétique Médicale (J.-J.S., J.-B.G., R.R.)., Skoric-Milosavljevic D; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC (Y.M., R.T., D.S.-M., E.A.N., A.A.M.W., C.R.B.), University of Amsterdam, the Netherlands., Nannenberg EA; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC (Y.M., R.T., D.S.-M., E.A.N., A.A.M.W., C.R.B.), University of Amsterdam, the Netherlands., Redon R; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; l'institut du thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., R.R., F.K.).; CHU Nantes, Service de Génétique Médicale (J.-J.S., J.-B.G., R.R.)., Papadakis M; Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.)., Kyndt F; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; l'institut du thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., R.R., F.K.).; l'institut du thorax, CHU Nantes, Service de Cardiologie, Nantes, France (F.K.)., Dagradi F; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics (L.C., F.D., S.C., M.T., P.J.S.), Milan, Italy., Castelletti S; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics (L.C., F.D., S.C., M.T., P.J.S.), Milan, Italy., Torchio M; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics (L.C., F.D., S.C., M.T., P.J.S.), Milan, Italy., Meitinger T; Helmholtz Zentrum München, Institute of Human Genetics, Neuherberg (T.M., P.L.).; Technische Universität München, Institute of Human Genetics (T.M.).; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (T.M.)., Lichtner P; Helmholtz Zentrum München, Institute of Human Genetics, Neuherberg (T.M., P.L.)., Ishikawa T; National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.)., Wilde AAM; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC (Y.M., R.T., D.S.-M., E.A.N., A.A.M.W., C.R.B.), University of Amsterdam, the Netherlands., Takahashi K; Kizawa memorial hospital, Gifu, Japan (K.T.)., Sharma S; Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.)., Roden DM; Vanderbilt University School of Medicine, Nashville, TN (D.M.R.)., Borggrefe MM; Department of Medicine, University Medical Center Mannheim (UMM), Faculty of Medicine Mannheim, University of Heidelberg, European Center for AngioScience (ECAS) & DZHK (German Center for Cardiovascular Research) partner site Heidelberg/Mannheim, Germany (M.M.B.)., McKeown PP; Belfast Health & Social Care Trust, United Kingdom (A.M., P.P.M.).; Queen's University Belfast, United Kingdom (P.P.M.)., Shimizu W; National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.).; Nippon Medical School, Tokyo, Japan (W.S.)., Horie M; Shiga University of Medical Science (S.O., M.H.)., Makita N; National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.)., Aiba T; National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.)., Ackerman MJ; Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (J.M.B., D.J.T., M.J.A.)., Schwartz PJ; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics (L.C., F.D., S.C., M.T., P.J.S.), Milan, Italy., Probst V; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Reference Center for hereditary arrhythmic diseases, Cardiologic Department and INSERM U1087, L'Institut du Thorax, Nantes, France (V.P.)., Bezzina CR; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).; Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC (Y.M., R.T., D.S.-M., E.A.N., A.A.M.W., C.R.B.), University of Amsterdam, the Netherlands., Behr ER; Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).; European Reference Network for Rare & Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart) (Y.D.W., Y.M., V.B., J.B., L.C., R.T., M.M., H.R., J.-J.S., J.-B.G., D.S.-M., E.A.N., R.R., M.P., F.K., F.D., S.C., M.T., A.A.M.W., S.S., P.J.S., V.P., C.R.B., E.R.B.).
Jazyk:	angličtina
Zdroj:	Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2020 Dec; Vol. 13 (6), pp. e002911. Date of Electronic Publication: 2020 Nov 09.
DOI:	10.1161/CIRCGEN.120.002911
Abstrakt:	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.
Databáze:	MEDLINE
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