期刊
CARDIOVASCULAR RESEARCH
卷 106, 期 3, 页码 520-529出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvv042
关键词
Brugada syndrome; Genetics; SCN10A; QRS duration; Rare variants
资金
- Higher Education Funding Council for England
- British Heart Foundation [PG/12/38/29615]
- French Ministry of Health P.H.R.C. [AOR 04070]
- Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program
- National Institute of Health [U19 HL65962, HL092217]
- MMPCMICROMouseGrant (MMPC/NIH)
- Netherlands Cardio-Vascular Research Initiative (PREDICT)
- Dutch Heart Foundation
- Dutch Federation of University Medical Centers
- Netherlands Organization for Health Research and Development
- Royal Netherlands Academy of Sciences
- CTMM
- Center for Translational Molecular Medicine
- project COHFAR [01C-203]
- Italian Ministry of Education, University and Research (MIUR) FIRB [RBFR12I3KA]
- Italian Ministry of Education, University and Research (MIUR) [PRIN 2010BWY8E9]
- Italian Ministry of Health [GR-2010-2305717]
- Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), University of Copenhagen, Denmark
- Laboratory of Molecular Cardiology, The Heart Centre
- Department of Cardiology, University Hospital Rigshospitalet, Copenhagen, Denmark
- John and Birthe Meyer Foundation
- British Heart Foundation [PG/12/38/29615] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [15K15311, 15H04823] Funding Source: KAKEN
Aims Brugada syndrome(BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. Methods and results A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10ASNPV1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR(95% CI) = 3.02 (2.35-3.87), P = 8.07 x 10-19]. Voltage-clamp experiments for Na(V)1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak I-Na compared with ancestral allele A1073 (rs6795970). Conclusion Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10AV1073 was strongly associated with BrS and demonstrated loss of Na(V)1.8 function, as did rare variants in isolated patients.
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