By: David Shifrin, PhD
Science Writer, Filament Life Science Communications

In 2009, over 10,500 deaths were caused by ruptured aortic aneurysms, while the same condition contributed to another 17,000. Aneurysms occur when a vessel wall weakens, causing a bulge like that seen in a water balloon squeezed in a fist. When the pressure becomes too great, the layers of the vessel can separate and allow blood in between them (dissection) or, the entire wall can rupture. With the volume of blood flowing through the aorta, either of these situations can be deadly.

The field has known for some time that aneurysms have a genetic component, with genes involved in building or maintaining connective tissue being of particular interest. There are a number of diseases and syndromes that involve aortic aneurysms, including the connective tissue disorders Marfan syndrome and Ehlers-Danlos syndrome. Fortunately, surgery can be performed to preempt aneurysms, with monitoring and testing allowing physicians to determine when intervention might be necessary. Among other things, specific genetic variants are indicators for preemptive surgery.

In July, a preliminary study on routine genetic testing for thoracic aortic aneurysm was presented as a poster at the Annual Meeting of The Society of Thoracic Surgeons and subsequently published in The Annals of Thoracic Surgery.

Slightly fewer than 200 individuals were enrolled in the study, with 102 having completed the process at the time of publication. Participants were primarily enrolled based on the presence or history of aortic aneurysm. Family history was also used as a relevant factor. Participants underwent whole exome sequencing, with a particular focus on 21 genes implicated in aortic aneurysm.

By utilizing WES, the investigators were able to uncover not only known mutations, but “suspicious” variants as well. Indeed, WES revealed variants in the 21 TAAD (thoracic aortic aneurysm and dissection) genes in about a quarter of the individuals tested. Only four variants were conclusively identified as pathogenic, with most of the others binned as being of unknown significance. This latter group, though not particularly helpful now, is valuable for identifying potentially relevant variants for future study.

In a few cases, the results of the original WES led investigators to test family members for specific mutations. A deleterious mutation was found in two members of one family, demonstrating the value of progressively testing from proband to related individuals when significant results are found in the former.

The authors of the study point out that their work allowed for personalized management in the patients based on each individual’s specific genetic profile. For example, “among patients found to harbor a mutation prone to dissect without severe aneurysmal dilatation […] a policy of more frequent imaging and earlier prophylactic surgery was applied.”

This is only a preliminary study on the utility and value of routine genetic testing for TAAD. However, the results do indicate that this approach may have significant clinical benefits. Additionally, as the authors point out, routine WES in patients with a personal or familial history of aortic aneurysms will help build the database of known variants, making genetic analysis all the more effective for patients in the future. Lastly, WES, unlike targeted Sanger sequencing, allows reanalysis of patients’ results as more pathogenic variants become known. For example, the data from the ~75% of participants in this study who did not display a variant known to be involved in TAAD, could be reassessed at a later date to aid in clinical management.

While there are still practical issues to deal with, such as insurance coverage (33 of the enrollees were denied coverage for testing and therefore did not undergo WES), this work does support the possibility of applying routine testing for known genetic diseases on a wider basis.

Tue. August 25, 2015