Investigators Link Genetic Mutation to TAA and Dissection

June 10, 2015—The European Society of Human Genetics (ESHG) announced that Elisabeth Gillis, MSc, presented evidence linking a particular genetic mutation to thoracic aortic aneurysm and dissection (TAAD). Gillis, who is a PhD candidate at the Centre for Medical Genetics at Antwerp University Hospital in Antwerp, Belgium, presented the findings at the ESHG’s annual conference, held June 6–9 in Glasgow, United Kingdom.

According to the ESHG, approximately one in five patients with TAAD has a family member with the same disorder, thereby indicating a genetic cause. However, the relevant genetic mutations discovered so far explain only approximately 30% of all cases.

Through the study of a large family with TAAD features, Ms. Gillis and an international team of genetic researchers discovered that a mutation in the TGFB3 gene is also responsible for the condition. The investigators are the first to link this particular genetic mutation to serious aortic disorders, noted the ESHG.

Ms. Gillis stated that these findings mean that the TGFB3 gene can be included in diagnostic screening. In the ESHG press release, she commented, “Armed with this knowledge, we can screen patients with symptoms of TAAD, and also family members without symptoms. Early identification of a risk of aortic aneurysm formation will allow us to implement preventive treatment with medication aimed at slowing down the process of aneurysm and, ultimately, replacement of the aorta before a significant risk of dissection arises.”

As summarized in the ESHG announcement, the investigators studied nine patients from a large Flemish-Dutch family with the cardiovascular, skeletal, and facial features typical of a form of TAAD, called Loeys-Dietz syndrome. They screened DNA from each family member without finding any genetic mutations known to be connected with TAAD at that stage. However, further investigation revealed two candidate genomic regions that appeared to be involved, one of which contained the TGBF3 gene. Ms. Gillis explained, “This gene was an obvious candidate because it has previously been shown that the TGFbeta-signaling pathway has a key role in the formation of aortic aneurysm.”

After sequencing the gene, the investigators identified a mutation that was present in all affected family members. Finally, 470 TAAD patients were screened for TGFB3 mutations, and causal mutations were found in ten other families.

Ms. Gillis commented, “This is an important finding because incidence of TAADs may be much higher than currently reported. Acute aortic dissections may be disguised as heart attacks, and we know that the genetic component of TAAD is strong—in about 20% of patients, it is also found in family members. Therefore, anything we can do to enable early identification of people at risk will help. However, aortic aneurysm formation is not yet fully understood, so reversing the risk of dissections remains a challenge, even though effective treatments are available.”

As noted in the ESHG press release, the choice of treatments for TAAD depends on a number of factors, such as size/location of the aneurysm and rate of growth. Current therapies include surgery, for example replacing the weakened part of the aorta, and medical treatments such as beta-blockers or angiotensin receptor blockers.

Ms. Gillis concluded, “Research on the TGFbeta-pathway in TAAD is far from finished. In addition to investigating further the role of these mutations in the condition, the discovery of new TGBF3 patients will help us improve follow-up guidelines for them. We hope that the identification of these new genetic factors will speed progress towards truly personalized medicine. The more we can link mutated genes to specific patients, the more we can identify the right symptoms and link specific therapies to them.”