Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant "Risk Variants".,American Journal of Human Genetics

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Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant "Risk Variants".
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2018-06-28 , DOI: 10.1016/j.ajhg.2018.05.012
Callie S Kwartler ₁ , Limin Gong ₁ , Jiyuan Chen ₁ , Shanzhi Wang ₁ , Richard Kulmacz ₂ , Xue-Yan Duan ₁ , Alexandra Janda ₁ , Jian Huang ₃ , Kristine E Kamm ₃ , James T Stull ₃ , Dongchuan Guo ₁ , Dianna M Milewicz ₁

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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 bothin vitroenzymatic assays and mouse models. VUSs inLOXandMYLKidentified 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, aMyh11variant, p.Arg247Cys, which does not cause aortic disease in either humans or mice, was crossed with theActa2−/−mouse, which has aortic enlargement with age whileActa2+/−mice do not.Acta2+/−Myh11R247C/R247Cmice 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. Furthermore, the addition ofMyh11R247C/R247Cto theActa2−/−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.

中文翻译：

与遗传性胸主动脉疾病相关的基因中未知意义的变异可能是低渗透的“风险变异”。

如果可以确定有危险的个体，导致急性主动脉夹层的胸主动脉瘤是可预防的过早死亡原因。没有家族史或综合征特征的早发性主动脉夹层的个体，在具有可遗传性胸主动脉疾病（HTAD）的病原体变异的基因中，具有未知意义的罕见遗传变异（VUSs）的负担增加。我们使用体外酶测定和小鼠模型评估了VUS在疾病发展中的作用。分析在急性主动脉夹层个体中鉴定的VUS inLOX和MYLK，以确定它们是否破坏了酶的活性。与野生型蛋白相比，VUS的一个子集降低了酶活性，但低于致病性变体。此外，还有Myh11variant，p.Arg247Cys，不会在人类或小鼠中引起主动脉疾病的小鼠与Acta2-/-小鼠杂交，后者随年龄增长而主动脉增大，而Acta2 +/-小鼠则没有。Acta2+/- Myh11R247C / R247C小鼠在3个月大时就具有主动脉扩张，而没有内侧变性，表明两个未知的引起疾病的变体确实导致主动脉扩大。此外，将Myh11R247C / R247C添加到Acta2-/-小鼠模型可加速主动脉扩大并增加内侧变性。因此，我们的结果强调，孟德尔基因变异的分类系统需要超越致病性，可能致病性，VUS，可能良性和良性的5层系统，并包括低渗透性“风险性变体”的名称。与其他危险因素结合或以随机方式触发疾病的疾病。

更新日期：2018-06-30

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