Inherited Aortic Disease: Expanding the Diagnostic Yield Using Next-Generation Sequencing

Objectives: Hereditary aortopathies, such as Marfan and Loeys-Dietz syndrome, cause up to 20% of thoracic aortic aneurysms. However, conventional testing of 18 known disease-associated genes identifies the genetic cause in only 10 to 25% of the patients with positive family history. This small diagnostic yield may be explained by a high number of so far unknown causal genes and genetic variants. Therefore, we aimed to reveal novel genetic variants and candidate genes that are associated with thoracic aortic aneurysm and hereditary connective tissue disease.

Methods: Using next-generation sequencing (NGS), we analyzed 44 candidate genes mainly encoding structural components of the connective tissue in 100 unrelated patients with suspected hereditary aortopathy or connective tissue disease. In these patients conventional genetic testing of 18 known disease genes was negative. Sequencing data underwent an in-depth bioinformatic analysis. Identified variants were classified according to their likelihood for pathogenicity (benign, likely benign, unknown significance, likely pathogenic, pathogenic) based on the ACMG and AMP guidelines on variant interpretation.

Result: Bioinformatic analysis identified a total of 183 candidate variants in 100 patients. Of these, nine variants in six different genes were classified as pathogenic or likely pathogenic. Six of these pathogenic variants were unknown before. Pathogenic mutations in collagen encoding genes (i.e., COL1A1, COL1A2, and COL2A1) account for 77.8% (7/9) of the (likely) pathogenic variants. An association of COL2A1 to aortic disease has not been reported before, thus we suggest COL2A1 as a novel disease-causing gene in hereditary aortopathy. Furthermore, we identified (likely) pathogenic variants in both SMAD4 and COL1A2 in one patient, indicating a possible digenic inheritance of a thoracoabdominal aortic aneurysm. Taken together, we could increase the diagnostic yield for hereditary aortopathies by 9%.

Conclusion: Conventional genetic testing for hereditary aortopathy fails to detect causal genetic variants in many patients. To expand the diagnostic yield, a larger NGS gene panel should be employed.

Publication History

Article published online:
19 February 2021