Targeted sequencing of human aorta tissue reveals undiagnosed heritable thoracic aortic disease

OBJECTIVES To diagnose undiagnosed Heritable Thoracic Aortic Disease (HTAD) using targeted Next-Generation Sequencing (NGS) technology on human aorta tissue obtained from a single-center biobank. METHODS From May 2016 to November 2021, 622 patients undergoing surgical repair for Thoracic Aortic Aneurysm (TAA) or Acute Aortic Syndrome (AAS) donated blood or tissue samples to the research biobank. 134 aortic tissue samples were retrieved from patients suspected of HTAD. The inclusion criteria were: 1) family history, 2) age ≤ 45, 3) annuloaortic ectasia, 4) bicuspid aortic valve, 5) patent ductus arteriosus, 6) polycystic kidney disease, or 7) patients previously classified as VUS (Variant of Uncertain Significance) by germline sequencing (n = 17). Exclusion criteria included patients previously classified as LP (Likely Pathogenic) or P (Pathogenic) by germline sequencing. The targeted panel included 96 genes. RESULTS Total 29 variants were identified including FBN1, MYH11, COL11A1, SMAD3, SMAD6, ACTA2, COL3A1, FLNA, PKD2, THSD4, ACVRL1 and FBN2. Total 27 patients (20.1%) had variants with 2 patients having digenic variants. Clinical data were combined with genetic data and finally 17 patients (12.7%) were additionally diagnosed with HTAD. CONCLUSIONS Genomic data analysis of human aortic tissue allowed for additional diagnoses of undiagnosed HTAD, contributing to resolving discrepancies between clinical and genomic data. Considering the surgical treatment of HTAD, human aortic tissue can be a valuable resource for genomic analysis.