Bhave Shreyas A, Guo Dong-Chuan, Angelov Stoyan, Bamshad Michael J, Nickerson Deborah A, Milewicz Dianna, Wallingford Mary C
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, US.
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, US.
Cardiogenetics. 2021 Sep;11(3):132-138. doi: 10.3390/cardiogenetics11030015. Epub 2021 Aug 18.
Thoracic aortic aneurysms (TAAs) that progress to acute thoracic aortic dissections (TADs) are life threatening vascular events that have been associated with altered transforming growth factor (TGF) β signaling. In addition to TAA, multiple genetic vascular disorders, including hereditary hemorrhagic telangiectasia (HHT), involve altered TGFβ signaling and vascular malformations. Due to the importance of TGFβ, genomic variant databases have been curated for activin receptor-like kinase 1 () and endoglin (). This case report details seven variants in that are associated with either heritable or early onset aortic dissections and compares them to pathogenic exon variants in gnomAD v2.1.1. The TAA and TAD variants were identified through whole exome sequencing of 346 unrelated heritable thoracic aortic disease (HTAD) and 355 individuals of early onset (age ≤ 56 years old) of thoracic aortic dissection (ESTAD). An allele frequency filter of less than 0.05% was applied in the Genome Aggregation Database (gnomAD exome v2.1.1) with a combined annotation dependent depletion score (CADD) greater than 20. These seven variants also have a higher REVEL score (>0.2), indicating pathogenic potential. Further and analysis is needed to evaluate how these variants affect mRNA stability and SMAD4 protein activity in association with thoracic aortic disease.
进展为急性胸主动脉夹层（TAD）的胸主动脉瘤（TAA）是危及生命的血管事件，与转化生长因子（TGF）β信号改变有关。除了TAA，多种遗传性血管疾病，包括遗传性出血性毛细血管扩张症（HHT），都涉及TGFβ信号改变和血管畸形。由于TGFβ的重要性，已针对激活素受体样激酶1（）和内皮糖蛋白（）建立了基因组变异数据库。本病例报告详细介绍了中与遗传性或早发性主动脉夹层相关的七个变异，并将它们与gnomAD v2.1.1中的致病性外显子变异进行了比较。通过对346例无关的遗传性胸主动脉疾病（HTAD）和355例早发性（年龄≤56岁）胸主动脉夹层（ESTAD）个体进行全外显子测序，鉴定出TAA和TAD变异。在基因组聚合数据库（gnomAD外显子v2.1.1）中应用了小于0.05%的等位基因频率过滤器，且综合注释依赖缺失评分（CADD）大于20。这七个变异的REVEL评分也更高（>0.2），表明具有致病潜力。需要进一步进行和分析，以评估这些变异如何影响与胸主动脉疾病相关的mRNA稳定性和SMAD4蛋白活性。
