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首页> 外文期刊>Circulation. Genomic and precision medicine. >Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes A Multi-Ancestry Analysis
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Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes A Multi-Ancestry Analysis

机译：罕见的编码变异有关心电图描记的间隔确定单基因心律失常Multi-Ancestry易感基因分析

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BACKGROUND: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS: Using a discovery sample of 29000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4x10:). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4x10 :5), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.
机译：背景:在心电图描记的改变(ECG)间隔是众所周知的标记心律失常和心脏性猝死(SCD)的风险。而心律失常综合征的基因研究之间的关系心电图描记的间隔和罕见的基因变化在人口水平差理解。29000人全基因组测序在精密医学和Trans-Omics与whole-exome复制000年近100从英国生物库和MyCode测序,我们研究低频和之间的联系罕见的编码变异5经常测量心电图描记的特征(RR,纵波、公关和QRS时间间隔和校正QT间隔)。结果:我们发现罕见变异相关与基于人群心电图时间间隔确定建立了单基因的化合物基因(KCNQ1、KCNH2 SCN5A),一个有争议的单基因SCD基因(KCNE1)和新基因(PAM和MFGE8)参与心脏传导。功能丧失和致病性SCN5A基因变异,由0.1%的个体,是相关的近3年来增加的可能性一度房室传导阻滞(P = 8.4 x10:)。类似的变体在KCNQ1和KCNH2(0.2%的个人)23倍增加的几率明显纠正QT间隔延长(P = 4 x10: 5), SCD危险的标记。不完全外显率这样的有害变化是常见的航空公司的70%以上正常心电图描记的间隔。结论:我们的发现表明大规模的最高深度序列数据和心电图描记的分析确定单基因心律失常易感基因罕见变异影响大。致病性变异在传统的心律失常和SCD基因不完全外显率和展出只占一小部分明显心电图描记的间隔延长。

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