Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland
Funding Information: This work was funded in part by grants from the Landspitali–The National University of Iceland Science Fund and the Helga Jonsdottir and Sigurlidi Kristjansson Memorial Fund. Publisher Copyright: © 2023 The Authors. Background Long-QT syndrome (LQTS) is a cardiac repolarization...
Published in: | Journal of the American Heart Association |
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2023
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Online Access: | https://hdl.handle.net/20.500.11815/4391 https://doi.org/10.1161/JAHA.123.029845 |
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Opin vísindi (Iceland) |
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Bráðahjúkrun Barnalæknisfræði Svæfinga- og gjörgæslulæknisfræði Hjartalæknisfræði genetic epidemiology genetics long‐QT syndrome precision medicine Cardiology and Cardiovascular Medicine |
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Bráðahjúkrun Barnalæknisfræði Svæfinga- og gjörgæslulæknisfræði Hjartalæknisfræði genetic epidemiology genetics long‐QT syndrome precision medicine Cardiology and Cardiovascular Medicine Sveinbjornsson, Gardar Benediktsdóttir, Bára Dís Sigfússon, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Ægisdóttir, Hildur Margrét Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnússon, Viðar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, Davíð Ottó Stefánsson, Kári Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland |
topic_facet |
Bráðahjúkrun Barnalæknisfræði Svæfinga- og gjörgæslulæknisfræði Hjartalæknisfræði genetic epidemiology genetics long‐QT syndrome precision medicine Cardiology and Cardiovascular Medicine |
description |
Funding Information: This work was funded in part by grants from the Landspitali–The National University of Iceland Science Fund and the Helga Jonsdottir and Sigurlidi Kristjansson Memorial Fund. Publisher Copyright: © 2023 The Authors. Background Long-QT syndrome (LQTS) is a cardiac repolarization abnormality that can lead to sudden cardiac death. The most common causes are rare coding variants in the genes KCNQ1, KCNH2, and SCN5A. The data on LQTS epidemiology are limited, and information on expressivity and penetrance of pathogenic variants is sparse. Methods and Results We screened for rare coding variants associated with the corrected QT (QTc) interval in Iceland. We explored the frequency of the identified variants, their penetrance, and their association with severe events. Twelve variants were associated with the QTc interval. Five in KCNQ1, 3 in KCNH2, 2 in cardiomyopathy genes MYBPC3 and PKP2, and 2 in genes where coding variants have not been associated with the QTc interval, ISOC1 and MYOM2. The combined carrier frequency of the 8 variants in the previously known LQTS genes was 530 per 100 000 individuals (1:190). p.Tyr315Cys and p.Leu273Phe in KCNQ1 were associated with having a mean QTc interval longer than 500 ms (P=4.2×10-7; odds ratio [OR], 38.6; P=8.4×10-10, OR, 26.5; respectively), and p.Leu273Phe was associated with sudden cardiac death (P=0.0034; OR, 2.99). p.Val215Met in KCNQ1 was carried by 1 in 280 Icelanders, had a smaller effect on the QTc interval (P=1.8×10-44; effect, 22.8 ms), and did not associate with severe clinical events. Conclusions The carrier frequency of associating variants in LQTS genes was higher than previous estimates of the prevalence of LQTS. The variants have variable effects on the QTc interval, and carriers of p.Tyr315Cys and p.Leu273Phe have a more severe disease than carriers of p.Val215Met. These data could lead to improved identification, risk stratification, and a more precise clinical approach to those with QTc prolongation. Peer reviewed |
author2 |
Other departments Faculty of Medicine |
format |
Article in Journal/Newspaper |
author |
Sveinbjornsson, Gardar Benediktsdóttir, Bára Dís Sigfússon, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Ægisdóttir, Hildur Margrét Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnússon, Viðar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, Davíð Ottó Stefánsson, Kári |
author_facet |
Sveinbjornsson, Gardar Benediktsdóttir, Bára Dís Sigfússon, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Ægisdóttir, Hildur Margrét Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnússon, Viðar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, Davíð Ottó Stefánsson, Kári |
author_sort |
Sveinbjornsson, Gardar |
title |
Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland |
title_short |
Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland |
title_full |
Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland |
title_fullStr |
Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland |
title_full_unstemmed |
Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland |
title_sort |
screening for rare coding variants that associate with the qtc interval in iceland |
publishDate |
2023 |
url |
https://hdl.handle.net/20.500.11815/4391 https://doi.org/10.1161/JAHA.123.029845 |
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Iceland |
genre_facet |
Iceland |
op_relation |
Journal of the American Heart Association; 12(14) http://www.scopus.com/inward/record.url?scp=85165223239&partnerID=8YFLogxK Sveinbjornsson , G , Benediktsdóttir , B D , Sigfússon , G , Norland , K , Davidsson , O B , Thorolfsdottir , R B , Tragante , V , Arnadottir , G A , Jensson , B O , Katrinardottir , H , Fridriksdottir , R , Gudmundsdottir , H , Ægisdóttir , H M , Fridriksson , B , Thorgeirsson , G , Magnússon , V , Oddsson , A , Sulem , P , Gudbjartsson , D F , Holm , H , Arnar , D O & Stefánsson , K 2023 , ' Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland ' , Journal of the American Heart Association , vol. 12 , no. 14 , e029845 , pp. e029845 . https://doi.org/10.1161/JAHA.123.029845 2047-9980 168606991 6b6fb3ca-3bf0-4851-9015-2a2ae19adc48 85165223239 37449562 https://hdl.handle.net/20.500.11815/4391 doi:10.1161/JAHA.123.029845 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/20.500.11815/439110.1161/JAHA.123.029845 |
container_title |
Journal of the American Heart Association |
container_volume |
12 |
container_issue |
14 |
_version_ |
1786206159475048448 |
spelling |
ftopinvisindi:oai:opinvisindi.is:20.500.11815/4391 2023-12-24T10:17:48+01:00 Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland Sveinbjornsson, Gardar Benediktsdóttir, Bára Dís Sigfússon, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Ægisdóttir, Hildur Margrét Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnússon, Viðar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, Davíð Ottó Stefánsson, Kári Other departments Faculty of Medicine 2023-07-18 1582370 e029845 https://hdl.handle.net/20.500.11815/4391 https://doi.org/10.1161/JAHA.123.029845 en eng Journal of the American Heart Association; 12(14) http://www.scopus.com/inward/record.url?scp=85165223239&partnerID=8YFLogxK Sveinbjornsson , G , Benediktsdóttir , B D , Sigfússon , G , Norland , K , Davidsson , O B , Thorolfsdottir , R B , Tragante , V , Arnadottir , G A , Jensson , B O , Katrinardottir , H , Fridriksdottir , R , Gudmundsdottir , H , Ægisdóttir , H M , Fridriksson , B , Thorgeirsson , G , Magnússon , V , Oddsson , A , Sulem , P , Gudbjartsson , D F , Holm , H , Arnar , D O & Stefánsson , K 2023 , ' Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland ' , Journal of the American Heart Association , vol. 12 , no. 14 , e029845 , pp. e029845 . https://doi.org/10.1161/JAHA.123.029845 2047-9980 168606991 6b6fb3ca-3bf0-4851-9015-2a2ae19adc48 85165223239 37449562 https://hdl.handle.net/20.500.11815/4391 doi:10.1161/JAHA.123.029845 info:eu-repo/semantics/openAccess Bráðahjúkrun Barnalæknisfræði Svæfinga- og gjörgæslulæknisfræði Hjartalæknisfræði genetic epidemiology genetics long‐QT syndrome precision medicine Cardiology and Cardiovascular Medicine /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article 2023 ftopinvisindi https://doi.org/20.500.11815/439110.1161/JAHA.123.029845 2023-11-29T23:55:20Z Funding Information: This work was funded in part by grants from the Landspitali–The National University of Iceland Science Fund and the Helga Jonsdottir and Sigurlidi Kristjansson Memorial Fund. Publisher Copyright: © 2023 The Authors. Background Long-QT syndrome (LQTS) is a cardiac repolarization abnormality that can lead to sudden cardiac death. The most common causes are rare coding variants in the genes KCNQ1, KCNH2, and SCN5A. The data on LQTS epidemiology are limited, and information on expressivity and penetrance of pathogenic variants is sparse. Methods and Results We screened for rare coding variants associated with the corrected QT (QTc) interval in Iceland. We explored the frequency of the identified variants, their penetrance, and their association with severe events. Twelve variants were associated with the QTc interval. Five in KCNQ1, 3 in KCNH2, 2 in cardiomyopathy genes MYBPC3 and PKP2, and 2 in genes where coding variants have not been associated with the QTc interval, ISOC1 and MYOM2. The combined carrier frequency of the 8 variants in the previously known LQTS genes was 530 per 100 000 individuals (1:190). p.Tyr315Cys and p.Leu273Phe in KCNQ1 were associated with having a mean QTc interval longer than 500 ms (P=4.2×10-7; odds ratio [OR], 38.6; P=8.4×10-10, OR, 26.5; respectively), and p.Leu273Phe was associated with sudden cardiac death (P=0.0034; OR, 2.99). p.Val215Met in KCNQ1 was carried by 1 in 280 Icelanders, had a smaller effect on the QTc interval (P=1.8×10-44; effect, 22.8 ms), and did not associate with severe clinical events. Conclusions The carrier frequency of associating variants in LQTS genes was higher than previous estimates of the prevalence of LQTS. The variants have variable effects on the QTc interval, and carriers of p.Tyr315Cys and p.Leu273Phe have a more severe disease than carriers of p.Val215Met. These data could lead to improved identification, risk stratification, and a more precise clinical approach to those with QTc prolongation. Peer reviewed Article in Journal/Newspaper Iceland Opin vísindi (Iceland) Journal of the American Heart Association 12 14 |