Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants
Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants
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DOI：
10.1161/jaha.119.013808
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发表时间：
2020-02-04
影响因子：
5.4
通讯作者：
McNally, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Pottinger, Tess D.;Puckelwartz, Megan J.;McNally, Elizabeth M.
基因组测序结合电子健康记录数据可以揭示医学上重要的遗传变异。罕见的遗传变异及其在介导心血管表型中的作用的解释被不确定意义的变异所混淆。方法和结果我们分析了来自美国单一中心的900名不同种族和民族的生物库参与者的全基因组序列。参与者平均分为欧洲人、非洲人、西班牙人和混血儿。我们评估了美国医学遗传学和基因组学学院医学上可操作的59个基因列表，重点是心脏基因。变异是使用ClinVar（一个医学相关人类变异数据库）的最新报告来解释的。我们确定了19例具有心脏可动基因致病性或可能致病性变异的个体（2%），并在电子健康记录中发现了相关临床相关性的证据。与欧洲血统的参与者相比，非洲血统的参与者在医学上可操作的基因中有更多不确定意义的变异，包括30个心脏可操作的基因，即使标准化到每人的总变异数。从大约400名生物库参与者（1723例患者年）中纵向测量左心室大小与遗传发现相关。在可操作的心脏基因中存在>= 1不确定变异和心肌病诊断与舒张期和收缩期左心室内径增加相关。特别是，MYBPC3被确定为具有不确定意义的过量变异的基因。结论：这些数据表明，一部分不确定的遗传变异可能会带来风险，不应被视为良性的。
BackgroundGenome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance.Methods and ResultsWe analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed races/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes, focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic or likely pathogenic variants in cardiac actionable genes (2%) and found evidence of related clinical correlates in the electronic health record. Participants of African ancestry, compared with those of European ancestry, had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size from approximate to 400 biobank participants (1723 patient-years) were correlated with genetic findings. The presence of >= 1 uncertain variant in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance.ConclusionsThese data indicate that a subset of uncertain genetic variants may confer risk and should not be considered benign.