Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.
J Cardiol. 2019 Aug;74(2):136-143. doi: 10.1016/j.jjcc.2019.03.014. Epub 2019 Apr 15.
Recent advances in DNA sequencing technology have identified several causative genes for hereditary thoracic aortic aneurysms and dissections (TAADs), including Marfan syndrome (MFS), Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and familial non-syndromic TAADs. Syndromic TAADs are typically caused by pathogenic variants in the transforming growth factor-β signal and extracellular matrix-related genes (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, and COL3A1). On the other hand, approximately 20% of the non-syndromic hereditary TAADs result from altered components of the contractile apparatus of vascular smooth muscle cells, which are encoded by ACTA2, MYH11, MYLK, and PRKG1 genes; however, the remaining 80% cannot be explained by previously reported candidate genes. Moreover, the relationship between the genotype and phenotype of TAADs has extensively been reported to investigate better methods for risk stratification and further personalized treatment strategies. With regard to MFS-causing FBN1, recent reports have shown significantly increased risk of aortic events in patients carrying a truncating variant or a variant exhibiting a haploinsufficient-type effect, typically comprising nonsense or small insertions/deletions resulting in out-of-frame effects, compared to those carrying a variant with dominant negative-type effect, typically comprising missense variants. Therefore, cardiologists are required to have sufficient knowledge regarding the genetics of hereditary TAADs for providing the best clinical management, with an appropriate genetic counseling. In the current review, we present current advances in the genetics of hereditary TAADs and discuss the benefits and limitations with respect to the use of this genetic understanding in clinical settings.
最近，DNA 测序技术的进步已经确定了几个导致遗传性胸主动脉瘤和夹层（TAAD）的致病基因，包括马凡综合征（MFS）、Loeys-Dietz 综合征、血管性埃勒斯-当洛斯综合征和家族性非综合征性 TAAD。综合征性 TAAD 通常由转化生长因子-β信号和细胞外基质相关基因（如 FBN1、TGFBR1、TGFBR2、SMAD3、TGFB2 和 COL3A1）的致病变体引起。另一方面，大约 20%的非综合征性遗传性 TAAD 是由于血管平滑肌细胞收缩装置的改变成分引起的，这些改变成分由 ACTA2、MYH11、MYLK 和 PRKG1 基因编码；然而，其余 80%不能用以前报道的候选基因来解释。此外，TAAD 的基因型和表型之间的关系已经广泛报道，以研究更好的风险分层方法和进一步的个性化治疗策略。关于导致 MFS 的 FBN1，最近的报告表明，携带截断变体或表现出杂合不足型效应的变体的患者发生主动脉事件的风险显著增加，与携带具有显性负型效应的变体的患者相比，典型地包括无义或小插入/缺失导致框架外效应的变体，典型地包括错义变体。因此，心脏病专家需要充分了解遗传性 TAAD 的遗传学，以便提供最佳的临床管理，并进行适当的遗传咨询。在当前的综述中，我们介绍了遗传性 TAAD 遗传学的最新进展，并讨论了在临床环境中利用这种遗传理解的益处和局限性。
