Rare genetic variants linked to bicuspid aortic valve disease identified in young adults

Genetic variants linked to a rare form of bicuspid aortic valve disease that affects young adults and can lead to dangerous and life-threatening aortic complications have been identified by UTHealth Houston researchers.

The study was published in the American Journal of Human Genetics.

“We have previously found that young individuals who present with early thoracic aortic dissections are more likely to have bicuspid aortic valves and more likely to have rare variants in genes associated with bicuspid aortic valves,” said Siddharth Prakash, MD, PhD, co-principal investigator of the study and associate professor of medical genetics and cardiovascular medicine in the department of internal medicine at McGovern Medical School at UTHealth Houston.

“When we observed that bicuspid aortic valve is a kind of risk marker for this group with poor outcomes, we specifically wanted to see if younger individuals who present clinically with problems related to bicuspid aortic valve disease may also have rare genetic variants that predict complications such as the need for valve surgery.”

About 1 in 100 people are born with a bicuspid aortic valve, making it the most common cause of congenital heart disease.

Comparing the rare subgroup of early-onset bicuspid aortic valve disease with the common disease population allowed researchers to determine which group of patients would benefit from genetic testing, allowing earlier and more aggressive treatment.

Patients with bicuspid aortic valve disease often wait too long to be seen, leading to more serious cardiovascular symptoms, such as heart failure and even sudden death, researchers say.

A bicuspid aortic valve is a congenital heart defect in which the valve has two flaps, or cusps, instead of three, so that the valve does not open and close properly with each heartbeat. This can lead to complications such as blockage, reduced or backed-up blood flow into the heart chambers, causing shortness of breath, chest pain, fainting, and difficulty exercising. In more severe cases, the condition can lead to aortic dissection, or tearing of the aorta, a potentially fatal condition.

The researchers studied individuals who had specific complications of the disease before age 30 or who were close relatives of someone with early-onset bicuspid aortic valve disease. Early-onset symptoms of the disease were defined as moderate or severe aortic stenosis or aortic regurgitation, a large thoracic aortic aneurysm, the need for aortic surgery, or aortic dissection.

The researchers sought to identify genetic variants that might lead to an increased risk of the disease in young adults. “In this study, the average person was affected in their 20s and had relatives with the disease. So we traced the onset of the disease in families and reported rare genetic variants that were associated with the disease in these participants and their relatives,” Prakash said.

Prakash and his team analyzed whole-exome sequencing data from 215 families from more than 20 institutions to identify rare genetic variants known to cause congenital heart disease in patients with early-onset bicuspid aortic valve disease in this rare subgroup. They compared these findings to those in the more common population of patients with late-onset bicuspid aortic valve disease.

The genes identified included genes responsible for isolated nonsyndromic bicuspid aortic valve disease, as well as other types of congenital heart disease associated with bicuspid aortic valve disease or related congenital malformations. The researchers found damaging genetic variants with moderate or strong evidence of causing developmental cardiac phenotypes in 107 affected families, or 50%.

“We showed that older patients with bicuspid aortic valves are unlikely to benefit from genetic testing because they are unlikely to have these types of genetic variants,” Prakash said.

“It is important for people to understand, as we have seen in this study, that many people with bicuspid aortic valve have relatives who are affected. In the future, family members could be tested for genetic variants that cause complications related to bicuspid aortic valve, and people with these genetic variants could be treated early to prevent future complications.”