Deconvoluting genomic variants associated with thoracic aortic disease in the 100,000 Genomes Project (360G-Wellcome-227508_Z_23_Z)

Diseases of the aorta (the largest blood vessel taking blood from the heart to the body) are often silent until a catastrophic life-threatening complication occurs, such as a tear or rupture. These diseases are frequently caused by changes in the genes (DNA) that can be passed down in families. We can now sequence, or read, the genetic makeup of individual patients but it is difficult to be sure which of the many variants (changes in the DNA sequence) are causing the disease. Our study will use stem cells in the lab, where we can introduce the DNA variant to see what effect it has on aortic smooth muscle cells (the cell types making up the aortic wall). In this way we will identify if the variants are harmful or not by comparing smooth muscle cells with and without the variant. We will aim to determine how the disease is caused and then test drug therapies to see if they improve the disease features. This work will allow us to better understand the variants that are being identified by genetic sequencing and provide more tailored medical advice for patients and their relatives on the cause of their disease and likely outcome.