Whole-Exome Sequencing Identified Genes Responsible for Thoracic Aortic Aneurysms and Dissections in three Chinese Families

Abstract

Thoracic aortic aneurysms and dissections are precarious conditions that often cannot be diagnosed with fatal outcomes. Over the last few years, pathogenic variants in numerous genes have been identified that predispose to heritable presentations of TAAD. An evidence-based strategy for the selection of genes to test in familial TAAD helps inform family screening and intervention to prevent life-threatening events. Using whole-exome sequencing, four members of three unrelated families clinically diagnosed with TAAD were used to identify the genetic origin of the disorder. Variant evaluation was carried out to detect the pathogenic mutation. Our studies suggest that mutations of COL3A1 and ACTA2 are responsible for familial TAAD. In addition, we highlight FBLN5, FBN1, SLC2A10, FBN2, and NOTCH1 as candidate genes. Future studies of crosstalk among the pathways may provide us a step toward understanding the pathogenic mechanism. This finding indicates the necessity of obtaining family medical history and screening of extended relatives of patients with TAAD for the early identification and treatment of TAAD.

Animal Models, Pathogenesis, and Potential Treatment of Thoracic Aortic Aneurysm

“…As the VSMC-elastin-contractile unit is vital in maintaining aortic integrity, defects in the proteins involved in the pathway could lead to TAA formation [24]. Indeed, many proteins are associated with TAAs in humans [155,[157][158][159][160][161][162][163][164][165][166][167][168][169][170], and some (fibrillin-1, fibulin-4, microfibrilassociated glycoprotein 1/2, lysyl oxidase, testin, thrombospondin domain containing 4, soluble guanylate cyclase, and cGMP-dependent protein kinase) have been confirmed as playing a causal role in TAA formation in animal models [80,88,97,[104][105][106]161,165,166,[171][172][173][174][175][176] (Table 7).…”

Animal Models and Pathogenesis of Thoracic Aortic Aneurysm

“…As the VSMC-elastin-contractile unit is vital in maintaining the aortic integrity, defects in the proteins involved in the pathway could lead to TAA formation [20]. Indeed, many proteins are associated with TAAs in humans [155,[157][158][159][160][161][162][163][164][165][166][167][168][169][170][171], and some (fibrillin-1, fibulin-4, microfibril-associated glycoprotein 1/2, lysyl oxidase, testin, thrombospondin domain containing 4, soluble guanylate cyclase, and cGMP-dependent protein kinase) have been confirmed to play a causal role in TAA formation in animal models [80,88,97,[104][105][106]161,165,166,[172][173][174][175][176][177] (Table 1).…”