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DOI: 10.1055/s-0044-1787954
Exome Sequencing of 1429 Patients with Thoracic Aortic Disease at the Yale Aortic Institute: what Have We Learned?
Objective: One in five cases of thoracic aortic aneurysm and dissection (TAAD) are familial. Although more than 60 genes (with varying degrees of evidence) have been implicated in causing TAAD, suspicious variants are found in only one-third of patients. Via exome sequencing of DNA samples from patients with thoracic aortic disease, we applied advanced gene searching techniques in an effort to identify additional causative genes for TAAD.
Methods: A total of 1429 patients with TAAD underwent exome sequencing. After quality control procedures, genomic data on 1278 unrelated TAAD patients of European ancestry were analyzed for enrichment in a case-control model for rare (allele frequency <10−4) deleterious missense (Dmis) and likely gene disrupting variants. This patient cohort (mean age 61±13, 72% male) consisted predominantly of patients with ascending aortic disease (1232, 96%). 433 (34%) patients had a bicuspid aortic valve (BAV), 124 (9.7%) experienced an aortic dissection event, and 22.7% had a positive family history. For the control group, we used 145,103 unrelated individuals of European ancestry from the UK BioBank. The fundamental principle of our gene search technique was to identify, via advanced genomic statistical methods, genes substantially “enriched” in our aneurysm patients compared to controls.
Results: The 24 ClinGen confirmed TAAD risk genes were analyzed using the American College of Medical Genetics and Genomics criteria. We identified 52 pathogenic or likely pathogenic variants in the currently known TAAD risk genes, signifying that these genes can explain only 4.1% of all TAAD cases. 75 more variants in these genes were classified as variants of uncertain significance (5.9%). Next, three potential novel candidate genes emerged from the unbiased case-control analysis, which utilized AlphaFold domain-based annotation of protein structure: VPS8 (p=8.8×10−9 for the β-propeller domain only), STAG2 (p=3.9 × 10−8), and UTP11 (p=3.9 × 10−8).
Conclusion: In a case-control association analysis, we have identified three promising novel candidate risk genes for TAAD (VPS8, STAG2, and UTP11), which merit further investigation and confirmation in other cohorts of patients with aortopathy. With each newly identified TAAD gene, a progressively greater proportion of TAAD cases are “explained” by underlying genetic causes.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
11 June 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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