Opin vísindi

Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland

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
Author: Sveinbjornsson, Gardar   orcid.org/0000-0003-2429-9468
Benediktsdóttir, Bára Dís
Sigfússon, Gunnlaugur
Norland, Kristjan
Davidsson, Olafur B.
Thorolfsdottir, Rosa B.
Tragante, Vinicius
Arnadottir, Gudny A.
Jensson, Brynjar O.
Katrinardottir, Hildigunnur
... 12 more authors Show all authors
Date: 2023-07-18
Language: English
Scope: e029845
Department: Internal Medicine and Emergency Services
Other departments
Faculty of Medicine
Series: Journal of the American Heart Association; 12(14)
ISSN: 2047-9980
DOI: https://doi.org/10.1161/JAHA.123.029845
Subject: Bráðahjúkrun; Barnalæknisfræði; Svæfinga- og gjörgæslulæknisfræði; Hjartalæknisfræði; genetic epidemiology; genetics; long‐QT syndrome; precision medicine; Cardiology and Cardiovascular Medicine
URI: https://hdl.handle.net/20.500.11815/4391

Show full item record


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


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.


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.

Files in this item

This item appears in the following Collection(s)