Interpreting secondary cardiac disease variants in an exome cohort.
Interpreting secondary cardiac disease variants in an exome cohort.
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DOI：
10.1161/circgenetics.113.000039
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发表时间：
2013-08
期刊：
影响因子：
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通讯作者：
NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program
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文献类型：
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作者：
Ng D;Johnston JJ;Teer JK;Singh LN;Peller LC;Wynter JS;Lewis KL;Cooper DN;Stenson PD;Mullikin JC;Biesecker LG;NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program
大规模平行测序鉴定罕见变异在医学研究和临床中广泛应用。基因组和外显子组测序可以确定疾病的遗传原因（主要结果），但也可以确定未被寻找的潜在疾病的致病变异（次要或偶然结果）。关于向研究参与者返还次要结果的问题引发了一场重大争议。我们已经试点了一种分析外显子组的方法，以识别有心律失常、心肌病或猝死风险的参与者。对870名没有选择心律失常、心肌病或猝死家族史的参与者进行了外显子组测序。使用一种算法对基因型质量、频率和数据库信息进行过滤，分析了来自22个心律失常和41个心肌病相关基因的外显子组数据。我们在心肌病基因中鉴定出1367个变异，在心律失常基因中鉴定出360个变异。6名参与者有与扩张型心肌病（n=1）、肥厚型心肌病（n=2）、左心室不致密化（n=1）或长QT综合征（n=2）相关的致病变异。其中两名参与者有心肌病的证据，一名在ECHO上有左心室不致密。三名可能有致病变异的参与者QTc延长。家族史包括亲属中不明原因的突然死亡。在这项研究中，大约0.5%的参与者在已知的心肌病或心律失常基因中有致病变异。这种高频率可能是由于自我选择、假阳性或低估了这些疾病的患病率。我们得出结论，临床上重要的心肌病和心律失常继发变异可以在未选择的外显子组中确定。
Massively parallel sequencing to identify rare variants is widely practiced in medical research and in the clinic. Genome and exome sequencing can identify the genetic cause of a disease (primary results), but can also identify pathogenic variants underlying diseases that are not being sought (secondary or incidental results). A major controversy has developed surrounding the return of secondary results to research participants. We have piloted a method to analyze exomes to identify participants at-risk for cardiac arrhythmias, cardiomyopathies or sudden death. Exome sequencing was performed on 870 participants not selected for arrhythmia, cardiomyopathy, or a family history of sudden death. Exome data from 22 cardiac arrhythmia and 41 cardiomyopathy-associated genes were analyzed using an algorithm that filtered results on genotype quality, frequency, and database information. We identified 1367 variants in the cardiomyopathy genes and 360 variants in the arrhythmia genes. Six participants had pathogenic variants associated with dilated cardiomyopathy (n=1), hypertrophic cardiomyopathy (n=2), left ventricular noncompaction (n=1) or long QT syndrome (n=2). Two of these participants had evidence of cardiomyopathy and one had left ventricular noncompaction on ECHO. Three participants with likely pathogenic variants had prolonged QTc. Family history included unexplained sudden death among relatives. Approximately 0.5% of participants in this study had pathogenic variants in known cardiomyopathy or arrhythmia genes. This high frequency may be due to self-selection, false positives, or underestimation of the prevalence of these conditions. We conclude that clinically important cardiomyopathy and dysrhythmia secondary variants can be identified in unselected exomes.