Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant "Risk Variants"
Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant "Risk Variants"
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DOI：
10.1016/j.ajhg.2018.05.012
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发表时间：
2018-07-05
影响因子：
9.8
通讯作者：
Milewicz, Dianna M.
中科院分区：
文献类型：
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作者：
Kwartler, Callie S.;Gong, Limin;Milewicz, Dianna M.
如果能够识别出高危个体，导致急性主动脉夹层的胸主动脉瘤是一种可预防的过早死亡原因。无家族史或综合征特征的早发性主动脉夹层患者在遗传性胸主动脉疾病（HTAD）致病变异基因中具有未知意义的罕见遗传变异（VUSs）的负担增加。我们使用体外酶分析和小鼠模型评估了VUSs在疾病发展中的作用。研究人员检测了急性主动脉夹层患者LOX和MYLK中的VUSs，以确定它们是否破坏了酶的活性。与野生型蛋白相比，VUSs的一个子集降低了酶活性，但低于致病变体。此外，Myh11变体p.a g247cys不会引起人类或小鼠的主动脉疾病，与Acta2（-/-）小鼠杂交，后者随着年龄的增长主动脉增大，而Acta2（+/-）小鼠则不会。Acta2(+/-)Myh11（R247C/R247C）小鼠在3个月大时主动脉扩张，但没有内侧退变，这表明两种未知致病变异确实会导致主动脉扩张。此外，在Acta2（-/-）小鼠模型中添加Myh11（R247C/R247C）会加速主动脉扩张并增加内侧退变。因此，我们的研究结果强调了对孟德尔基因变异的分类系统的需求，该系统需要超越致病、可能致病、VUS、可能良性和良性的5层系统，并包括对低渗透“风险变异”的指定，这些变异要么与其他风险因素结合，要么以随机方式触发疾病。
Thoracic aortic aneurysms leading to acute aortic dissections are a preventable cause of premature deaths if individuals at risk can be identified. Individuals with early-onset aortic dissections without a family history or syndromic features have an increased burden of rare genetic variants of unknown significance (VUSs) in genes with pathogenic variants for heritable thoracic aortic disease (HTAD). We assessed the role of VUSs in the development of disease using both in vitro enzymatic assays and mouse models. VUSs in LOX and MYLK identified in individuals with acute aortic dissections were assayed to determine whether they disrupted enzymatic activity. A subset of VUSs reduced enzymatic activity compared to the wild-type proteins but less than pathogenic variants. Additionally, a Myh11 variant, p.Arg247Cys, which does not cause aortic disease in either humans or mice, was crossed with the Acta2(-/-) mouse, which has aortic enlargement with age while Acta2(+/-) mice do not. Acta2(+/-)Myh11(R247C/R247C) mice have aortic dilation by 3 months of age without medial degeneration, indicating that two variants not known to cause disease do lead to aortic enlargement in combination. Further-more, the addition of Myh11(R247C/R247C) to the Acta2(-/-) mouse model accelerates aortic enlargement and increases medial degeneration. Therefore, our results emphasize the need for a classification system for variants in Mendelian genes that goes beyond the 5-tier system of pathogenic, likely pathogenic, VUS, likely benign, and benign, and includes a designation for low-penetrant "risk variants" that trigger disease either in combination with other risk factors or in a stochastic manner.