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

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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.