Rationale: Thoracic aortic aneurysm (TAA) leads to substantial mortality worldwide. Familial and syndromic TAAs are highly correlated with genetics. However, the incidence of sporadic isolated TAA (iTAA) is much higher, and the genetic contribution is not yet clear.
Objective: Here, we examined the genetic characteristics of sporadic iTAA.
Methods and results: We performed a genetic screen of 551 sporadic iTAA cases and 1071 controls via whole-exome sequencing. The prevalence of pathogenic mutations in known causal genes was 5.08% in the iTAA cohort. We selected 100 novel candidate genes using a strict strategy, and the suspected functional variants of these genes were significantly enriched in cases compared with controls and carried by 60.43% of patients. We found more severe phenotypes and a lower proportion of hypertension in cases with pathogenic mutations or suspected functional variants. Among the candidate genes, Testin (TES), which encodes a focal adhesion scaffold protein, was identified as a potential TAA causal gene, accounting for 4 patients with 2 missense variants in the LIM1 domain (c.751T>C encoding p.Y251H; c.838T>C encoding p.Y280H) and highly expressed in the aorta. The 2 variants led to a decrease in TES expression. The thoracic aorta was spontaneously dilated in the TesY249H knock-in and Tes-/- mice. Mechanistically, the p.Y249H variant or knockdown of TES led to the repression of vascular smooth muscle cell contraction genes and disturbed the vascular smooth muscle cell contractile phenotype. Interestingly, suspected functional variants of other focal adhesion scaffold genes, including TLN1 (Talin-1) and ZYX (zyxin), were also significantly enriched in patients with iTAA; moreover, their knockdown resulted in decreased contractility of vascular smooth muscle cells.
Conclusions: For the first time, this study revealed the genetic landscape across iTAA and showed that the focal adhesion scaffold genes are critical in the pathogenesis of iTAA.
Keywords: focal adhesion; genetic variation; phenotype; thoracic aortic aneurysm; vascular smooth muscle.