Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

Elijah R. Behr; Eleonora Savio-Galimberti; Julien Barc; Anders G. Holst; Evmorfia Petropoulou; Bram P. Prins; Javad Jabbari; Margherita Torchio; Myriam Berthet; Yuka Mizusawa; Tao Yang; Eline A. Nannenberg; Federica Dagradi; Peter Weeke; Rachel Bastiaenan; Michael J. Ackerman; Stig Haunso; Antoine Leenhardt; Stefan Kääb; Vincent Probst; Richard Redon; Sanjay Sharma; Arthur Wilde; Jacob Tfelt-Hansen; Peter Schwartz; Dan M. Roden; Connie R. Bezzina; Morten Olesen; Dawood Darbar; Pascale Guicheney; Lia Crotti; UK10K Consortium; Yalda Jamshidi

doi:10.1093/cvr/cvv042

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

Elijah R. Behr, Eleonora Savio-Galimberti, Julien Barc, Anders G. Holst, Evmorfia Petropoulou, Bram P. Prins, Javad Jabbari, Margherita Torchio, Myriam Berthet, Yuka Mizusawa, Tao Yang, Eline A. Nannenberg, Federica Dagradi, Peter Weeke, Rachel Bastiaenan, Michael J. Ackerman, Stig Haunso, Antoine Leenhardt, Stefan Kääb, Vincent ProbstRichard Redon, Sanjay Sharma, Arthur Wilde, Jacob Tfelt-Hansen, Peter Schwartz, Dan M. Roden, Connie R. Bezzina, Morten Olesen, Dawood Darbar, Pascale Guicheney, Lia Crotti, UK10K Consortium, Yalda Jamshidi

72 Citationer (Scopus)

Abstract

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 SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for Na_V1.8 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 SCN10A V1073 was strongly associated with BrS and demonstrated loss of Na_V1.8 function, as did rare variants in isolated patients.

Originalsprog	Engelsk
Tidsskrift	Cardiovascular Research
Vol/bind	106
Udgave nummer	3
Sider (fra-til)	520-529
Antal sider	10
ISSN	0008-6363
DOI	https://doi.org/10.1093/cvr/cvv042
Status	Udgivet - 1 jun. 2015

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10.1093/cvr/cvv042

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Behr, E. R., Savio-Galimberti, E., Barc, J., Holst, A. G., Petropoulou, E., Prins, B. P., Jabbari, J., Torchio, M., Berthet, M., Mizusawa, Y., Yang, T., Nannenberg, E. A., Dagradi, F., Weeke, P., Bastiaenan, R., Ackerman, M. J., Haunso, S., Leenhardt, A., Kääb, S., ... Jamshidi, Y. (2015). Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovascular Research, 106(3), 520-529. https://doi.org/10.1093/cvr/cvv042

Behr, ER, Savio-Galimberti, E, Barc, J, Holst, AG, Petropoulou, E, Prins, BP, Jabbari, J, Torchio, M, Berthet, M, Mizusawa, Y, Yang, T, Nannenberg, EA, Dagradi, F, Weeke, P, Bastiaenan, R, Ackerman, MJ, Haunso, S, Leenhardt, A, Kääb, S, Probst, V, Redon, R, Sharma, S, Wilde, A, Tfelt-Hansen, J, Schwartz, P, Roden, DM, Bezzina, CR, Olesen, M, Darbar, D, Guicheney, P, Crotti, L, UK10K Consortium & Jamshidi, Y 2015, 'Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study', Cardiovascular Research, bind 106, nr. 3, s. 520-529. https://doi.org/10.1093/cvr/cvv042

@article{600b11a39b0d452abaf48ce1bb7d3e87,

title = "Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study",

abstract = "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 SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 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 INa 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 SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.",

keywords = "Action Potentials, Adult, Aged, Brugada Syndrome, Case-Control Studies, Cell Line, Computational Biology, DNA Mutational Analysis, Databases, Genetic, Europe, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Heredity, Humans, Male, Middle Aged, NAV1.8 Voltage-Gated Sodium Channel, Odds Ratio, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Saudi Arabia, Transfection, United States",

author = "Behr, {Elijah R.} and Eleonora Savio-Galimberti and Julien Barc and Holst, {Anders G.} and Evmorfia Petropoulou and Prins, {Bram P.} and Javad Jabbari and Margherita Torchio and Myriam Berthet and Yuka Mizusawa and Tao Yang and Nannenberg, {Eline A.} and Federica Dagradi and Peter Weeke and Rachel Bastiaenan and Ackerman, {Michael J.} and Stig Haunso and Antoine Leenhardt and Stefan K{\"a}{\"a}b and Vincent Probst and Richard Redon and Sanjay Sharma and Arthur Wilde and Jacob Tfelt-Hansen and Peter Schwartz and Roden, {Dan M.} and Bezzina, {Connie R.} and Morten Olesen and Dawood Darbar and Pascale Guicheney and Lia Crotti and {UK10K Consortium} and Yalda Jamshidi",

year = "2015",

month = jun,

day = "1",

doi = "10.1093/cvr/cvv042",

language = "English",

volume = "106",

pages = "520--529",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "3",

}

TY - JOUR

T1 - Role of common and rare variants in SCN10A

T2 - results from the Brugada syndrome QRS locus gene discovery collaborative study

AU - Behr, Elijah R.

AU - Savio-Galimberti, Eleonora

AU - Barc, Julien

AU - Holst, Anders G.

AU - Petropoulou, Evmorfia

AU - Prins, Bram P.

AU - Jabbari, Javad

AU - Torchio, Margherita

AU - Berthet, Myriam

AU - Mizusawa, Yuka

AU - Yang, Tao

AU - Nannenberg, Eline A.

AU - Dagradi, Federica

AU - Weeke, Peter

AU - Bastiaenan, Rachel

AU - Ackerman, Michael J.

AU - Haunso, Stig

AU - Leenhardt, Antoine

AU - Kääb, Stefan

AU - Probst, Vincent

AU - Redon, Richard

AU - Sharma, Sanjay

AU - Wilde, Arthur

AU - Tfelt-Hansen, Jacob

AU - Schwartz, Peter

AU - Roden, Dan M.

AU - Bezzina, Connie R.

AU - Olesen, Morten

AU - Darbar, Dawood

AU - Guicheney, Pascale

AU - Crotti, Lia

AU - UK10K Consortium

AU - Jamshidi, Yalda

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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 SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 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 INa 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 SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

AB - 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 SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 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 INa 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 SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

KW - Action Potentials

KW - Adult

KW - Aged

KW - Brugada Syndrome

KW - Case-Control Studies

KW - Cell Line

KW - Computational Biology

KW - DNA Mutational Analysis

KW - Databases, Genetic

KW - Europe

KW - Female

KW - Gene Frequency

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Heredity

KW - Humans

KW - Male

KW - Middle Aged

KW - NAV1.8 Voltage-Gated Sodium Channel

KW - Odds Ratio

KW - Pedigree

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Saudi Arabia

KW - Transfection

KW - United States

U2 - 10.1093/cvr/cvv042

DO - 10.1093/cvr/cvv042

M3 - Journal article

C2 - 25691538

SN - 0008-6363

VL - 106

SP - 520

EP - 529

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 3

ER -

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

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