Ron Lacro, MD, was studying birth defects and genetics as a fellow in the 1980s, “we were just beginning to learn that genes are important for cardiac patients without syndromes,” he says.  At the time, the prevailing wisdom was that genetics played a pivotal role in cardiac-related syndromes such as Down syndrome and Noonan syndrome, but the evidence to suggest that genes were important for other kinds of cardiac issues such as isolated heart defects was less clear.

Lacro was intrigued by the intersection of two previously distinct areas of medicine: pediatric cardiology and genetics.  Immediately after completing his fellowship in Cardiology at Boston Children’s Hospital in 1991, Lacro launched the department’s Cardiovascular Genetics Program. The Program provides comprehensive cardiac and genetic care for individuals and families with heart disease.  Lacro is most interested in connective tissue disorders that involve the heart and blood vessels, including Marfan syndrome, Loeys-Dietz syndrome, bicuspid aortic valve, and familial aortic aneurysm and dissection.

Today, the program’s team includes four full time staff physicians, including Amy Roberts, MD, Director of Cardiovascular Genetics Research, Michael Singh, MD who specializes in adults with connective tissue disorders, and Leslie Smoot, MD, who manages individuals and families with cardiomyopathies, as well as syndromic and non-syndromic congenital heart disease.

Roberts started in pediatrics and then became interested in genetics.  Her specialty is Noonan syndrome, which is second only to Down syndrome as the most common genetic cause of congenital heart disease.

In the early 2000s, we didn’t know any of the genes that caused Noonan syndrome,” Roberts says.  “Today, we know of eight that explain about 80% of cases- and we can look for mutations in all of them with just one test.”

While the technology and research has been advancing by leaps and bounds over the past few decades, many specialists are still reluctant to incorporate genetic testing into their practice.

“We have come a long way,” says Roberts, “and as a group, pediatric cardiologists are increasingly aware of the need for genetic evaluations and counseling.  But many may still be hesitant to refer or bring up the subject with their patients. One reason could be that genetic evaluations for these diseases were simply not an option until recent years.   It’s also a difficult and potentially uncomfortable conversation.”

Roberts says many of her patient’s parents were told that their child’s heart problem was not genetic. “People should know that the recurrence risk is not negligible,” she says.  “For certain conditions, if one parent carries the genetic defect, the risk of another child also having the defect can be as high as 50%.”

Advancing research

Lacro and Roberts point out that many of their colleagues at the Heart Center are also doing great work in the realm of genetics. Leslie Smoot, MD, is studying the genetic component of congenital heart disease, and Dominic Abrams, MD, has designed a family arrhythmia clinic that heavily incorporates genetic testing.  There is a lot of work with genetics going on in the cardiomyopathy and heart failure programs as well. Additionally, there is also an active and highly successful basic science research group overseen by David Clapham, MD, PhD, that includes Vassilios Bezzerides, MD, PhD, John Kheir, MD, Bill Pu, MD, and Dazhi Wang, PhD.

The Heart Center is part of a multi-center Pediatric Cardiac Genetic Consortium (PCGC) that was created in 2009 to advance cardiovascular genetic research in pediatrics.  Together with Brigham and Women’s, Boston Children’s represents “the Boston site” (MA); other sites are Icahn School of Medicine at Mt. Sinai Hospital (NY), Columbia University (NY), Yale University (CT), Children’s Hospital of Philadelphia (PA), Gladstone Institutes (CA),  and University of Utah (UT).

The PCGC collaboration was momentous because gathering robust genetic data about pediatric heart disease is extremely challenging.  It can be hard to get good data about these diseases because they are so rare, and many people simply try a medical regimen without enrolling in a clinical trial.  And of course, “People are not mice,” says Roberts.  “Human clinical trials are important because the human genome is so much more complicated when compared to work done in research mice that have genetically identical backgrounds”

What’s next for the field?

Currently, identifying a gene can help doctors identify the cause of a disease.  But that alone doesn’t change long-term outcomes.  “We are now at the point where our research can develop drugs and other therapies to treat the problem or outcome caused by that identified gene,” says Lacro.

“We can figure out if a gene turns a genetic pathway up or down,” explains Roberts.  “What we want to do is address the downstream effect of a genetic mutation.”

Lacro and colleagues in the National Institutes of Health (NIH) funded Pediatric Heart Network recently completed an interventional drug trial involving children and young adults with Marfan syndrome.  Last December, his study comparing two commonly prescribed medications for Marfan syndrome— losartan and atenolol— was chosen as one of the year’s top ten cardiovascular research advances by the American Heart Association.  The study found that both drugs were effective in reducing the rate of growth of the aorta, but there was no marked difference in effectiveness between the two medications.  The work continues with studies to identify genetic and other factors that influence how an individual patient responds to one drug or the other.

Roberts says there is a new impetus to uncover the intersection of heart disease and neurodevelopment.  “We know that the genetic components of CHD are also related to neurodevelopmental outcomes,” she says.  “Unpacking that relationship is one of the PCGC’s recently launched initiatives.”