Paper of the Month: Unraveling the complex genetics of congenital heart disease

"Understanding the genetic underpinnings of congenital heart defects has been challenging.  Drs. Maslen and Ackerman have used an incisive experimental approach to demonstrate a linkage between heart defects in Down syndrome and mutations in several genes that converge on the VEGF pathway. Not only does this supply mechanistically important information for the field of developmental cardiology, but it illustrates the importance of effectively bringing together a variety of critically important experimental tools to address complex clinical problems.  In this case, the strategy included a multi-institutional collaboration, careful patient phenotyping, targeted sequencing and careful analytical bioinformatics — a winning combination."

- Eric Orwoll, M.D.
 Associate Dean for Clinical Science

This month's featured paper is from the laboratory of Dr. Cheryl Maslen, and is titled, "An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects." It was published in the The American Journal of Human Genetics.

Paper of MonthCongenital heart defects (CHD) are the most commonly occurring birth defect. In the United States, nearly 1 in 100 children are born with a heart malformation—many requiring surgery.

Atrioventricular septal defect (AVSD), a type of CHD, is a clinically severe heart problem that most frequently appears in children born with Down syndrome (DS), also known as trisomy 21. It occurs when there's a hole between the heart's chambers, which causes an increased flow of blood to the lungs. The defect can overwork the heart and cause it to enlarge, ultimately leading to heart failure. The problem does not resolve with time and most children must undergo heart surgery.

However, the problems don't always end there. While surgical repairs are critical to saving the lives of children with CHD, understanding the genetic make-up of what causes the heart malformation is equally crucial for long-term outcomes. "Some individuals with repaired CHD develop serious heart problems later in life," said Christine Ackerman, Ph.D., a postdoc in the Department of Medicine. "One reason may be that although the heart defect is repaired, the underlying genetic cause remains. These genes often play dual roles in guiding heart formation during development, and also in helping to maintain the heart throughout life."

Scientists know very little about the genetic underpinnings of AVSD, which according to the National Down Syndrome Project, affect about 20 percent of newborns with DS. In fact, 50 percent to 65 percent of infants with Down syndrome have a heart defect, which is well above the incidence of about 1 percent for the general population. "We think that trisomy 21 predisposes the developing heart to malformation, but does not alone cause heart defects," said Cheryl Maslen, Ph.D., professor of medicine whose major research is focused on the determining the molecular genetic basis of congenital heart defects. "We hypothesized studying heart defects in the context of DS would make it easier to find the other causative genes because the large impact of trisomy 21 pushes the individual closer to the disease threshold.

paper2120712However, amassing a sufficiently large cohort for genetic studies is challenging and requires teamwork, so Dr. Maslen developed a collaboration with investigators at Emory and Johns Hopkins Universities, which became the National Down Syndrome Heart Project. These groups collectively created the largest research-based registry of individuals with DS in the world. "We focused on AVSD because it is the single most common heart malformation in children with DS, and it is in general a clinically severe defect," said Dr. Maslen. "It is recognized that the genetics underlying AVSD are quite complex, so it made sense to study it in a population where one major risk factor was known, giving us an advantage in identifying the additional contributing genes."

Researchers in the Maslen Laboratory identified the first known single genetic risk factor for AVSD in 2003, and in subsequent years showed that rare variants in that gene (CRELD1) contribute to AVSD in otherwise normal individuals, kids with DS, and in individuals with another genetic disorder known as heterotaxy syndrome. Most recently, the team proved that variants that alter CRELD1 function increased the risk of AVSD.

In their recent study, titled "An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects," published in The American Journal of Human Genetics, the Maslen team found that about 30 percent of individuals with DS and AVSD have a genetic variant in one of six different genes—an important discovery because these variants change how the protein products work and these alterations affect heart development. 

"These genes have not been implicated in CHD before," said Dr. Ackerman, lead author on the paper. "They all affect a common biochemical pathway, which opens new routes to understanding how CHD occurs. As a result, now that we know the underlying pathway we can focus our efforts to identify all of the genetic components that combine to cause AVSD."

"This study is the single most significant advance to date in understanding the pathogenesis of AVSD, yet we still have quite a ways to go to understand the exact causes of this serious heart malformation," said Dr. Maslen. "We are currently planning additional genetic analyses to identify all of the genetic variants involved. New genetic methods, such as whole genome sequencing, will provide the team with the complete genetic profile for AVSD and could lead to therapeutic targets."

In recent decades, advances in surgery have dramatically increased survival rates. As a result, individuals with heart defects are now living to have children of their own, and in some cases passing on their genetic defects to their offspring, thus perpetuating an increase in the incidence of CHD. For investigators like Drs. Maslen and Ackerman, knowing the genetic basis of heart malformations will lead to a better understanding of who is at risk for future heart problems and the risk to future generations. 

Moving forward in their research, the Maslen team also wants to understand how environmental factors may influence who does and does not end up with a heart malformation like AVSD. This includes an interest in disparities in research and health care. The team is working to expand their studies into under-represented minority populations particularly since studies have shown that there are significant differences in susceptibility to heart defects. According to Dr. Maslen, studies have shown that African American children with DS are twice as likely to have an AVSD as Caucasian children: "We are interested in understanding why. Are there genetic differences that make them more susceptible? Or do environmental factors (including socio-economic status) influence this outcome?"

"One in 700 kids is born with DS, yet they receive disproportionately little attention in biomedical research," said Dr. Maslen. "By participating in our study they have made a significant contribution to research that will impact all people born with a heart defect. We believe that individuals with DS deserve to benefit from the many advances in medicine, and hope to address this disparity by bringing them into the research mainstream."


Pictured: (both pictures from left) Dr. Ackerman and Dr. Maslen

Paper Authors

Christine Ackerman, Ph.D.
Adam E. Locke, Ph.D.
Eleanor Feingold, Ph.D.
Benjamin Reshey, B.S.
Karina Espana, B.S.
Janita Thusberg, Ph.D.
Sean Mooney, Ph.D.
Lora J.H. Bean, Ph.D.
Kenneth J. Dooley, M.D.
Clifford L. Cua, M.D.
Roger H. Reeves, Ph.D.
Stephanie L. Sherman, Ph.D.
Cheryl L. Maslen, Ph.D.


The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.

More Published Papers

The entire list of OHSU papers published this month is here.