Skip to main content
Premium Trial:

Request an Annual Quote

Congenital Cardiac Union


In some cases, a collaborative approach is required not just to optimize funding but also because of the rarity of a disease. Such is the case with the Pediatric Cardiac Genomics Consortium, which, along with its sister project the Cardiovascular Development Consortium, is aimed at identifying the genetic and epigenetic causes of human congenital heart disease in order to connect genetic variants present in the congenital heart disease patient population to clinical outcomes. The PCGC is supported by a $25 million, six-year grant from the National Heart, Lung, and Blood Institute and includes researchers from Columbia University, Children's Hospital of Philadelphia, Mount Sinai School of Medicine, Yale University, the Children's Hospital Boston, and Brigham and Women's Hospital. "While we're all referral centers, and we see a large number of kids with congenital heart disease, this isn't something as common as something like diabetes," says Amy Roberts, an assistant professor in pediatrics at Harvard Medical School, who is leading the recruitment of new patients and collection of DNA. "To do whole-genome association studies really requires that you are well aware of large numbers and the only way to get those kinds of numbers is to pool the resources of centers that do a lot of this." She adds: "This kind of analysis just wouldn't be possible for a single center to do because none of us have numbers to support that." While rare, congenital heart defects affect eight out of every 1,000 infants. Several genetic causes of congenital heart disease are already known to researchers, but the consortium intends to focus on undiscovered genes.

In addition to the primary goal of identifying genes important to cardiac development for the purposes of understanding why some families have a predisposition to congenital heart disease, there is also a second, slightly more complex area of focus, Roberts says. Knowing which genes lead to congenital heart disease might help researchers unravel the role of those genes in normal and abnormal heart development. "The first six years are going to be much more concentrated on identifying these genes, and that will definitely open the door to doing more detailed analysis of function and how changes in the proteins really are important to changes in cardiac development," Roberts says.

Data and sample access

The inherent challenges to uniting several collaborators are many, including the regulatory issues related to sharing samples among centers with proper consent from the patients. Ironing out all of these details will take time and is the primary order of business within the first year of the grant. "Getting five centers to have a protocol that all of the centers approve of — we're trying to coordinate that, and it's not that these things won't happen, but they have to be thought about quite carefully," Roberts says. "Other issues are things like some of us use different -computer systems for things like coding for echocardiograms, and it's obviously very important to link the cardiac phenotype with each sample, so trying to unify the way that information is saved for each sample so that it can be centralized for access."

It goes without saying that this kind of analysis creates a huge amount of data. In addition to a protocol subcommittee, Roberts says the members of the PCGC have also formed a bioinformatics subcommittee and are in the early stages of determining the best place to save that data and how to allow all of the centers to have access to it. To assist with this process, the members of the PCGC are working with the New England Research Institutes, which is responsible for the organizational, behind-the-scenes work of putting documents together.

Working together

As with any collaboration, it'll be critical to develop efficient strategies of communication and to recruit the right people and resources to operate as points of contact for the sites involved. "Each center has a team of investigators, so each center has lots of people associated with the study and we've identified a few people at each center who are on a steering committee, and they meet by teleconference once every two weeks," Roberts says. "The NHLBI has also set up a website where we post documents that we need to review, protocols, and statements of work as a way to have a centralized location to give each other feedback and we discuss them by conference call."

While the researchers from each institution would normally be siloed away — possibly competing for grant money and not necessarily sharing data — being part of such a large-scale effort requires that investigators reach beyond their modi operandi. "I think [this collaboration] does in some way turn on its head the way that all of us have been doing this research because you have to think about things in a different way, which means doing things that are [not] just best for you but for the group at large," Roberts says. "Even though our center may be interested in one particular area of congenital heart development, other centers are interested in other areas. So we will use our resources from the grant to collect samples on children for whom other centers might be doing the most detailed analysis, as part of our contribution — even though it might not be benefiting the analysis that we do. We will be helping other centers do their analysis and the same goes for them; they will be collecting samples that we will use."

Ultimately, all involved are thinking not only about what will be the best for helping them answer their own research questions, but also about the best way to help the whole group resolve its research questions. Roberts says this is a different way of approaching her research. "The technology has gotten to the point of looking at [such] large groups that we have to do it this way. We can't really do it in individual groups anymore. We really need to have large enough numbers to say meaningful things, and that's in part because congenital heart genetics is not straightforward," she says. "There are variable penetrants, variable expressivity, and there are obviously epigenetic factors that are influencing cardiac development. We need to have a lot more cases to know what are true variants, what is pathogenic, and what the penetrance is of variants that we think are pathogenic."

The Breakdown
Members: Children's Hospital Boston, Brigham and Women's Hospital, Yale University, Mount Sinai School of Medicine, Columbia University, and Children's Hospital of Philadelphia.
Funding Source: National Heart, Lung, and Blood Institute
Amount: $25,440,000, total amount of projected award for the six-year period

The Scan

LINE-1 Linked to Premature Aging Conditions

Researchers report in Science Translational Medicine that the accumulation of LINE-1 RNA contributes to premature aging conditions and that symptoms can be improved by targeting them.

Team Presents Cattle Genotype-Tissue Expression Atlas

Using RNA sequences representing thousands of cattle samples, researchers looked at relationships between cattle genotype and tissue expression in Nature Genetics.

Researchers Map Recombination in Khoe-San Population

With whole-genome sequences for dozens of individuals from the Nama population, researchers saw in Genome Biology fine-scale recombination patterns that clustered outside of other populations.

Myotonic Dystrophy Repeat Detected in Family Genome Sequencing Analysis

While sequencing individuals from a multi-generation family, researchers identified a myotonic dystrophy type 2-related short tandem repeat in the European Journal of Human Genetics.