Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing

Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening pathology and remains challenging worldwide. Up to 40% of TAAD are hereditary with complex heterogeneous genetic backgrounds. Recently, next-generation sequencing (NGS) has been successfully applied to identify genetic variants in an efficient and cost-effective manner. In our study, NGS coupled with DNA target-capture array was used to screen 11 known causative genes of TAAD in 70 patients from Southern China. All the identified variants were confirmed by Sanger sequencing. We identified forty variants in 36 patients (51.4%), including three known pathogenic (7.5%), 10 likely pathogenic variants (25%, 9 in FBN1, 1 in ACTA2), and 27 variants with uncertain significance (VUS) (67.5%). Among the 27 VUS, 14 (51.9%) were in the FBN1 gene, 3 in Col5A2, 2 in ACTA2, 2 in MYH11, 2 in MYLK, 2 in SLC2A10, 1 in MSTN and 1 in SMAD3 respectively. Based on the segregation data and independent reports, five known likely pathogenic variants and four VUS were upgraded to pathogenic variant and likely pathogenic variant respectively. Our data indicate that NGS is a highly efficient genetic method for identification of pathogenic variants in TAAD patients.