Genetic Misdiagnoses and the Potential for Health Disparities.
Genetic Misdiagnoses and the Potential for Health Disparities.
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DOI：
10.1056/nejmsa1507092
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发表时间：
2016-08-18
期刊：
影响因子：
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通讯作者：
Kohane IS
中科院分区：
文献类型：
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作者：
Manrai AK;Funke BH;Rehm HL;Olesen MS;Maron BA;Szolovits P;Margulies DM;Loscalzo J;Kohane IS
十多年来，肥厚型心肌病的风险分层已通过靶向基因检测得到加强。使用测序结果，临床医生常规评估患者亲属患肥厚型心肌病的风险，并诊断临床表现不明确的患者的病情。然而，基因检测的好处伴随着变异可能被错误分类的风险。使用公开的外显子组数据，我们确定了以前被认为是肥厚性心肌病的因果关系，并在一般人群中过度代表的变异。我们在不同人群中研究了这些变异，并重新评估了它们在医学文献中的初步确定。我们回顾了一家领先的基因检测实验室在近十年的实验室历史中发生这些变异的患者记录。多名患者（均为非洲人或未指明血统）收到了阳性报告，根据检测时的理解，变异被错误归类为致病性。随后，所有报告的变异被重新归类为良性。在一般人群中最常见的突变在美国黑人中比在白色美国人中更常见（P<0.001）。模拟实验表明，即使在对照组中包括少量的美国黑人，也可能会防止这些错误的分类。我们确定了导致医学文献中这些错误的方法学缺陷。我们在研究中发现的将良性变异误分类为致病性的现象表明，需要对不同人群的基因组进行测序，包括无症状对照人群和受试患者人群。这些结果扩展了当前的指南，该指南建议使用祖先匹配的对照来解释变异。随着对不同祖先背景的其他人群进行测序，我们预计变异重新分类会增加，特别是对于历史上研究较少的祖先群体。（由美国国立卫生研究院资助。
For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient’s relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified. Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory. Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature. The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.)