Identification of clinically relevant variants by whole exome sequencing in Chinese patients with sporadic non-syndromic type A aortic dissection

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease, of which genetic abnormalities are considered as important risk factors. The present research aims at identifying causal variants in Chinese patients with sporadic non-syndromic type A TAAD (ATAAD).

Materials and methods: Whole exome sequencing (WES) was performed on 73 sporadic Chinese patients with ATAAD, 30 TAAD associated genes were curated for bioinformatic analyses. Clinical differences were compared between patients with and without causal variants.

Results: 15 pathogenic/likely pathogenic variants were identified (8 novel and 7 previously described) in 4 known TAAD-causal genes (FBN1, TGFBR2, SMAD3 and ACTA2) in 15 individuals, including 11 variants in FBN1 (7 missense, 3 truncating, and 1 splicing variants), 2 missense variants in TGFBR2, 1 ACTA2 frameshift variant and 1 SMAD3 frameshift variant. Significant clinical differences were found between patients with and without causal variants. Patients with TAAD-causal variants proved to have an earlier onset age, a more dilated aorta, and relatively intractable subtypes. Even without risk factor like hypertension, they might still suffer from TAAD with TAAD-causal variants.

Conclusions: The variants identified in our research might not only result in the occurrence of ATAAD, but also add complexities and difficulties to the clinical practice. Our data demonstrated that WES was an effective tool for determining genetic etiologies of non-syndromic ATAAD and could be helpful in genetic counseling for ATAAD patients and their at-risk family members.