Identification of coding and non-coding mutations causative for hereditary aortopathies

遗传性胸主动脉病变在临床上是异质性的，从非综合征型胸主动脉瘤和夹层（TAAD）类型到综合征型。为了避免危及生命的并发症，强烈建议进行分子遗传学诊断，以便计划进一步的治疗策略。对600多名患者进行的面板测序显示，其中只有约20%的患者存在致病突变。我们在这里提出了全基因组测序（WGS）的200个临床选择的个人从我们的队列作为一个“一个测试所有”的解决方案，以确定编码，非编码，和结构改变影响迄今未知的脊椎病疾病基因。为了补充这些分析，我们将从15名非TAAD对照和来自我们队列的多达45名患者的主动脉组织中进行RNA-seq。此外，我们计划ATAC和ChIP-seq来识别非TAAD主动脉组织、平滑肌细胞和主动脉成纤维细胞中的调控元件。拟议的项目旨在揭示与主要受影响组织相关的调节元件和基因表达谱。此外，这些数据将用于更好地解释非编码DNA变异，这将最终导致新的诊断选择和改善医疗保健，而不仅仅是TAAD患者。

Hereditary aortopathies are clinically heterogeneous, ranging from the non-syndromic thoracic aortic aneurysm and dissection (TAAD) types to syndromic conditions. To avoid life-threatening complications, a molecular genetic diagnosis is strongly recommended in order to plan further treatment strategies. Panel sequencing in more than 600 patients revealed a causative mutation in only about 20% of them. We propose here whole genome sequencing (WGS) of 200 clinically selected individuals from our cohort as a "One Test for All" solution to identify coding, non-coding, and structural alterations affecting hitherto unknown aortopathy disease genes. To complement these analyses, we will perform RNA-seq from aortic tissue of 15 non-TAAD controls and up to 45 patients from our cohort. Additionally, we plan ATAC- and ChIP-seq to identify regulatory elements in non-TAAD aortic tissue, smooth muscle cells and aortic fibroblasts. The proposed project aims to uncover regulatory elements and gene expression profiles relevant for the primarily affected tissue in aortopathies. Besides, the data will be used to establish better interpretation of non-coding DNA variants, which will eventually lead to novel diagnostic options and an improvement in health care not only for TAAD patients.