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Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland
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 pathog...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382112/ https://www.ncbi.nlm.nih.gov/pubmed/37449562 http://dx.doi.org/10.1161/JAHA.123.029845 |
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author | Sveinbjornsson, Gardar Benediktsdottir, Bara D. Sigfusson, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Aegisdottir, Hildur M. Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnusson, Vidar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, David O. Stefansson, Kari |
author_facet | Sveinbjornsson, Gardar Benediktsdottir, Bara D. Sigfusson, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Aegisdottir, Hildur M. Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnusson, Vidar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, David O. Stefansson, Kari |
author_sort | Sveinbjornsson, Gardar |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10382112 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103821122023-07-29 Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland Sveinbjornsson, Gardar Benediktsdottir, Bara D. Sigfusson, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Aegisdottir, Hildur M. Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnusson, Vidar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, David O. Stefansson, Kari J Am Heart Assoc Original Research 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. John Wiley and Sons Inc. 2023-07-14 /pmc/articles/PMC10382112/ /pubmed/37449562 http://dx.doi.org/10.1161/JAHA.123.029845 Text en © 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Sveinbjornsson, Gardar Benediktsdottir, Bara D. Sigfusson, Gunnlaugur Norland, Kristjan Davidsson, Olafur B. Thorolfsdottir, Rosa B. Tragante, Vinicius Arnadottir, Gudny A. Jensson, Brynjar O. Katrinardottir, Hildigunnur Fridriksdottir, Run Gudmundsdottir, Hallbera Aegisdottir, Hildur M. Fridriksson, Brynjar Thorgeirsson, Gudmundur Magnusson, Vidar Oddsson, Asmundur Sulem, Patrick Gudbjartsson, Daniel F. Holm, Hilma Arnar, David O. Stefansson, Kari Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland |
title | 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_short | 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 |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382112/ https://www.ncbi.nlm.nih.gov/pubmed/37449562 http://dx.doi.org/10.1161/JAHA.123.029845 |
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