Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes

Laura Andreasen; Gustav Ahlberg; Chuyi Tang; Charlotte Andreasen; Jacob P Hartmann; Jacob Tfelt-Hansen; Elijah R Behr; Steen Pehrson; Stig Haunsø; null LuCamp; Peter E Weeke; Thomas Jespersen; Morten S Olesen; Jesper H Svendsen

doi:10.1038/s41431-017-0092-0

Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes

Laura Andreasen, Gustav Ahlberg, Chuyi Tang, Charlotte Andreasen, Jacob P Hartmann, Jacob Tfelt-Hansen, Elijah R Behr, Steen Pehrson, Stig Haunsø, LuCamp, Peter E Weeke, Thomas Jespersen, Morten S Olesen, Jesper H Svendsen

4 Citationer (Scopus)

Abstract

Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.

Originalsprog	Engelsk
Tidsskrift	European Journal of Human Genetics
Vol/bind	26
Sider (fra-til)	660–668
ISSN	1018-4813
DOI	https://doi.org/10.1038/s41431-017-0092-0
Status	Udgivet - 1 maj 2018

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10.1038/s41431-017-0092-0

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Andreasen, L., Ahlberg, G., Tang, C., Andreasen, C., Hartmann, J. P., Tfelt-Hansen, J., Behr, E. R., Pehrson, S., Haunsø, S., LuCamp, Weeke, P. E., Jespersen, T., Olesen, M. S., & Svendsen, J. H. (2018). Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes. European Journal of Human Genetics, 26, 660–668. https://doi.org/10.1038/s41431-017-0092-0

Andreasen, L, Ahlberg, G, Tang, C, Andreasen, C, Hartmann, JP, Tfelt-Hansen, J, Behr, ER, Pehrson, S, Haunsø, S, LuCamp, Weeke, PE, Jespersen, T , Olesen, MS & Svendsen, JH 2018, 'Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes', European Journal of Human Genetics, bind 26, s. 660–668. https://doi.org/10.1038/s41431-017-0092-0

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title = "Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes",

abstract = "Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.",

author = "Laura Andreasen and Gustav Ahlberg and Chuyi Tang and Charlotte Andreasen and Hartmann, {Jacob P} and Jacob Tfelt-Hansen and Behr, {Elijah R} and Steen Pehrson and Stig Hauns{\o} and LuCamp and Weeke, {Peter E} and Thomas Jespersen and Olesen, {Morten S} and Svendsen, {Jesper H}",

year = "2018",

month = may,

day = "1",

doi = "10.1038/s41431-017-0092-0",

language = "English",

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pages = "660–668",

journal = "European Journal of Human Genetics",

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TY - JOUR

T1 - Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes

AU - Andreasen, Laura

AU - Ahlberg, Gustav

AU - Tang, Chuyi

AU - Andreasen, Charlotte

AU - Hartmann, Jacob P

AU - Tfelt-Hansen, Jacob

AU - Behr, Elijah R

AU - Pehrson, Steen

AU - Haunsø, Stig

AU - LuCamp, null

AU - Weeke, Peter E

AU - Jespersen, Thomas

AU - Olesen, Morten S

AU - Svendsen, Jesper H

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.

AB - Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.

U2 - 10.1038/s41431-017-0092-0

DO - 10.1038/s41431-017-0092-0

M3 - Journal article

C2 - 29396561

SN - 1018-4813

VL - 26

SP - 660

EP - 668

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

ER -

Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes

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