New variants in the genes of connective tissue components in a patient with ascending aortic aneurysm

Background. Along with common risk factors for cardiovascular disease (male gender, hypertension, smoking) the predisposition to the development of ascending aortic aneurysm is also largely determined by genetic factors. The genetic variants underlying the development of ascending aortic aneurysm are localized in the genes of connective tissue components, smooth muscle cell function, and the TGF-β signaling pathway. However, to date, a panel of genetic markers recommended for assessing the risk of developing sporadic cases of ascending aortic aneurysm has not yet been fully developed.

Aim: to determine clinically significant genetic variants in a patient with a sporadic ascending aortic aneurysm using the massively parallel sequencing.

Methods. We searched for rare genetic variants (minor allele frequency <1%) localized in exons of 53 genes of hereditary and syndromic forms of ascending aortic aneurysm in peripheral blood DNA of a patient (48 years old, diameter of the ascending aorta 50 mm). Clinical exome sequencing was performed on the SOPHiA GENETICS platform. Variant annotation was performed using the ANNOVAR program. Classification of variants according to the degree of pathogenicity was carried out according to the standards and recommendations of the American College of Medical Genetics (ACMG) using the VarSome tool with further validation of identified variants by Sanger sequencing.

Results. The sequencing revealed three variants of uncertain significance (VUS) in the following genes: FBN1 c.C7841T (p.A2614V), COL3A1 c.A2498T (p.K833I), and PLOD3 c.G833A (rs1041461490, p.G278D). Detected variants were not previously reported in relation with ascending aortic aneurysm. Two variants are localized in genes with a proven maximum effect of mutations on the development of ascending aortic aneurysm (FBN1, COL3A1). The third gene, PLOD3, is associated with diseases of the ascending aorta based on experimental studies, but in clinical practice its role in the development of ascending aortic aneurysm has not yet been established. Conclusion. Sporadic ascending aortic aneurysms have the same underlying pathogenic pathways as hereditary and syndromic forms. However, the combination of genetic variants found in sporadic cases is unique. To identify these distinctive features in patients with sporadic ascending aortic aneurysm genetic testing using an advanced panel is required. The development of extended genetic panel is a challenge for specialists in cardiogenetics.

1. Deng J., Li D., Zhang X., et al. Murine model of elastase-induced proximal thoracic aortic aneurysm through a midline incision in the anterior neck. Front Cardiovasc Med. 2023 Feb 6;10:953514.

2. Howard D.P.J., Banerjee A., Fairhead J.F., et al. Population-Based Study of Incidence and Outcome of Acute Aortic Dissection and Premorbid Risk Factor Control. Circulation. 2013 May 21;127(20):2031–7.

3. Salmasi M.Y., Alwis S., Cyclewala S., et al. The genetic basis of thoracic aortic disease: The future of aneurysm classification? Hell J Cardiol. 2023;69:41–50.

4. Bhandari R., Aatre R.D., Kanthi Y. Diagnostic approach and management of genetic aortopathies. Vasc Med. 2020 Feb 1;25(1):63–77.

5. Verstraeten A., Luyckx I., Loeys B. Aetiology and management of hereditary aortopathy. Nat Rev Cardiol. 2017 Apr;14(4):197–208.

6. Weerakkody R., Ross D., Parry D.A., et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med Off J Am Coll Med Genet. 2018 Nov;20(11):1414–22.

7. Arnaud P., Hanna N., Benarroch L., et al. Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). Genet Med Off J Am Coll Med Genet. 2019 Sep;21(9):2015–24.

8. Milewicz D.M., Guo D., Hostetler E., et al. Update on the genetic risk for thoracic aortic aneurysms and acute aortic dissections: implications for clinical care. J Cardiovasc Surg (Torino). 2021 Jun;62(3):203–10.

9. Rodrigues Bento J., Meester J., Luyckx I., et al. The Genetics and Typical Traits of Thoracic Aortic Aneurysm and Dissection. Annu Rev Genomics Hum Genet. 2022 Aug 31;23:223–53.

10. Ewans L.J., Colley A., Gaston-Massuet C., et al. Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications. J Med Genet. 2019 Sep;56(9):629–38.

11. Renard M., Francis C., Ghosh R., et al. Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. J Am Coll Cardiol. 2018 Aug 7;72(6):605–15.

12. Kontopodis N., Pantidis D., Dedes A., et al. The – Not So – Solid 5.5 cm Threshold for Abdominal Aortic Aneurysm Repair: Facts, Misinterpretations, and Future Directions. Front Surg. 2016 Jan 25;3:1.

13. Sazonova S.I., Saushkin V.V., Panfilov D.S., et al. Insights into ascending aortic aneurysm: Interactions between biomechanical properties of the aortic wall and tissue biomarkers. Heliyon. 2024 Jan 15;10(1):e23538.

14. Koenig S.N., Cavus O., Williams J., et al. New mechanistic insights to PLOD1-mediated human vascular disease. Transl Res J Lab Clin Med. 2022 Jan;239:1–17.

15. Li Y., Gao S., Han Y., et al. Variants of Focal Adhesion Scaffold Genes Cause Thoracic Aortic Aneurysm. Circ Res. 2021 Jan 8;128(1):8–23.

16. Guo D.C., Hostetler E.M., Fan Y., et al. Heritable Thoracic Aortic Disease Genes in Sporadic Aortic Dissection. J Am Coll Cardiol. 2017 Nov 28;70(21):2728–30.

17. Reddy P., Nair K.S., Kumar V., et al. Thoracic Aortic Aneurysmal Disease: Comprehensive Recommendations for the Primary Care Physician. Mayo Clin Proc. 2024 Jan;99(1):111–23.

18. Brownstein A.J., Kostiuk V., Ziganshin B.A., et al. Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications. Aorta Stamford Conn. 2018 Feb;6(1):13–20.

19. Versbraegen N., Gravel B., Nachtegael C., et al. Faster and more accurate pathogenic combination predictions with VarCoPP2.0. BMC Bioinformatics. 2023 May 1;24(1):179.

20. Kwartler C.S., Gong L., Chen J., et al. Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant “Risk Variants.” Am J Hum Genet. 2018 Jul 5;103(1):138–43.