Direct Inspection of Primary Aortic Cell Transcriptomes Identifies Candidate Causative Variants in Patients with Thoracic Aortic Aneurysm

Background: Thoracic aortic aneurysm (TAA) is an aortopathy that predisposes to life-threatening dissection. Autosomal dominant disorders associated with TAA include Marfan syndrome (FBN1), Loeys-Dietz (TGFBR1/2, SMAD3, TGFB2), and vascular type Ehlers-Danlos (COL3A1). Our objective was identify single nucleotide variants (SNVs) in these six genes within the transcriptomes of primary cells acquired from patients aortopathy.Methods: Primary cell lines were cultured directly medial layer surgically explanted tissues 63 unrelated patients. RNA samples extracted for mRNA sequencing. reads aligning 6 selected inspected using Integrative Genomics Viewer (Broad Institute), identified SNVs filtered downstream analysis.Results: Study predominantly male European ancestry a mean age 52±18 years. Thirty-three (52%) had bicuspid valve, 10 (16%) family history or A total 3740 patient transcriptomes, occurred at 905 distinct genomic coordinates. There 115 unique cohort, not located 3’-untranslated region, ≥20 aligned SNV’s position. Using application Franklin (Genoox) estimate clinical interpretation, 8 classified as pathogenic (P) likely (LP). Five P/LP reduced allelic expression, gene expression level below 20th percentile study SNVs. Eighty-six uncertain significance (VUSs). 39 (62%) least one SNV P/LP/VUS.
 Conclusion: Transcriptomic analysis candidate causative their relative expression. Further analyses will investigate additional TAA-associated integrate transcriptional abnormalities genetic variants.