Invitae Corporation , San Francisco, CA , USA.
Front Cardiovasc Med. 2016 Jun 27;3:20. doi: 10.3389/fcvm.2016.00020. eCollection 2016.
Advances in DNA sequencing have made large, diagnostic gene panels affordable and efficient. Broad adoption of such panels has begun to deliver on the promises of personalized medicine, but has also brought new challenges such as the presence of unexpected results, or results of uncertain clinical significance. Genetic analysis of inherited cardiac conditions is particularly challenging due to the extensive genetic heterogeneity underlying cardiac phenotypes, and the overlapping, variable, and incompletely penetrant nature of their clinical presentations. The design of effective diagnostic tests and the effective use of the results depend on a clear understanding of the relationship between each gene and each considered condition. To address these issues, we developed simple, systematic approaches to three fundamental challenges: (1) evaluating the strength of the evidence suggesting that a particular condition is caused by pathogenic variants in a particular gene, (2) evaluating whether unusual genotype/phenotype observations represent a plausible expansion of clinical phenotype associated with a gene, and (3) establishing a molecular diagnostic strategy to capture overlapping clinical presentations. These approaches focus on the systematic evaluation of the pathogenicity of variants identified in clinically affected individuals, and the natural history of disease in those individuals. Here, we applied these approaches to the evaluation of more than 100 genes reported to be associated with inherited cardiomyopathies and arrhythmias including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia or cardiomyopathy, long QT syndrome, short QT syndrome, Brugada, and catecholaminergic polymorphic ventricular tachycardia, and to a set of related syndromes such as Noonan Syndrome and Fabry disease. These approaches provide a framework for delivering meaningful and accurate genetic test results to individuals with hereditary cardiac conditions.
DNA 测序技术的进步使得大型诊断基因面板的价格变得实惠且高效。此类面板的广泛采用开始兑现个性化医疗的承诺，但也带来了新的挑战，例如出现意外结果或结果具有不确定的临床意义。由于心脏表型的遗传异质性广泛，以及其临床表现的重叠、多变和不完全外显率，遗传性心脏疾病的遗传分析尤其具有挑战性。有效的诊断测试的设计和结果的有效利用取决于对每个基因与每个考虑的疾病之间关系的清晰理解。为了解决这些问题，我们开发了简单、系统的方法来应对三个基本挑战：（1）评估特定疾病是否由特定基因中的致病性变体引起的证据强度；（2）评估不寻常的基因型/表型观察结果是否代表与基因相关的临床表型的合理扩展；（3）建立一种分子诊断策略来捕捉重叠的临床表现。这些方法侧重于系统评估在临床受影响个体中鉴定的变体的致病性，以及这些个体中疾病的自然史。在这里，我们将这些方法应用于评估 100 多个报告与遗传性心肌病和心律失常相关的基因，包括肥厚型心肌病、扩张型心肌病、致心律失常性右室发育不良或心肌病、长 QT 综合征、短 QT 综合征、Brugada 和儿茶酚胺多形性室性心动过速，以及一组相关综合征，如 Noonan 综合征和 Fabry 病。这些方法为遗传性心脏疾病患者提供了一个有意义且准确的遗传测试结果的框架。
