Dr. Gary Gibbons, Director, NHLBI:  Could you just address potentially what these observations mean for potentially other birth defects? And probably more importantly, what do you see as the future research efforts along these lines?

Dr. Richard Lifton, Yale University:  Sure. So one of the surprising observations in our study is that congenital heart disease is really the second disease for which large scale sequencing efforts have been taken on to try to identify genes contributing to common congenital malformations. 

The other disease is autism, and autism obviously is a neurodevelopmental disorder and it consequently came as a surprise that there appears to be significant overlap in the pathways that are mutated in autism and congenital heart disease. Just as one example, the gene that is most frequently mutated in autism is another gene in the histone 3 lysine 4 methylation pathway, suggesting that this pathway may play a role in a wide variety of congenital abnormalities. So one doesn’t need a lot of imagination to think that it will be important to look at this pathway in detail in all of the abnormalities of the major organ systems that cause congenital anomalies. So we think that is actually quite tantalizing.

Another aspect of our recent study is that it allowed us, for the first time, to begin making estimates as to how many genes are there likely to be that contribute to the overall burden of congenital heart disease. And that number is not 2, 5, or 10. It appears that there are likely to be hundreds of genes that when mutated cause, or strongly influence the development of congenital heart disease. So that tells us that we’re at the top of a fairly deep well and there’s going to be a lot to do to put together the genes and pathways. And we can begin to see from some of the other genes that were mutated in our first study that there are other pathways that are likely to emerge as we go further down the pipe in discovering the genes that contribute to this disease. And certain genes that are involved in the introduction of ubiquitin tags, which frequently target proteins for degradation, that’s a pathway that kind of has peeked its head above the water and suggests that this may turn out to play a significant role in this disease, as well.

And we expect that there will be a number of pathways as we get farther into this that emerge. I think one of the really exciting aspects of the work thus far is that it shows that this approach is going to be highly productive in elucidating the fundamental mechanisms that contribute to congenital heart disease.

Dr. Gibbons:  Yeah. Sort of in that regard of the impact, as a clinician scientist, I’m sure you’re motivated to translate discovery sciences into something that affects patients. And so could you speak a little bit about what would be the implications of the finding of this most recent paper on taking care of children either at risk or families at risk or children in the early stage of congenital heart disease? What are the potential clinical implications of this?

Dr. Lifton:  Sure. So certainly, we’ve already touched on the long-term possibility that we’ll gain insight into how to ultimately prevent these diseases. And as you well know, we do our best in medicine in prevention and treatment when we understand the underlying biology in intimate detail. So I think part of our job as biomedical scientists is to do the very best we can to understand the fundamental causes of the important human diseases. And ultimately, we would like to understand all diseases in the greatest detail possible. And so I think, part of living in one’s time is we’re in the time where there’s unprecedented opportunity for understanding the fundamental causes, making no assumptions about where that might lead us in therapeutics and prevention. 

But in a more tangible way in the context of congenital heart disease for today, one of the things that we know well is that patients who show up with ostensibly the same congenital heart disease go to the operating room, get their congenital heart disease corrected so that their heart is now ostensibly working in a proper fashion. And yet, recognizing that many of these patients have different outcomes in the long run. And we haven’t understood that well. One of the things that I think we are likely to find is that their outcomes vary depending upon which particular genes were mutated to lead to the development of the cardiac abnormality.

So an ability to predict that, recognize it, and hopefully, develop new treatment strategies where we might be able to prospectively identify patients who we think will do very well after surgery. And then, alternatively, patients who we can correct the heart defect but are going to have other problems that we can predict prospectively and begin working on how to prevent complications arising as a consequence of these different mutations that lead to ostensibly the same heart defect.

I should also mention one of the very practical aspects of this with patients is we frequently are asked on a counseling basis, “I’ve had a child with congenital heart disease. What is my risk for having another child with congenital heart disease?” And to the extent that we can tell parents that this child had a de novo mutation that caused the disease, you are at no greater risk for having another child with congenital heart disease than anyone else in the population, that obviously would have immediate impact on parents. 
SEGMENT 2: Dr. Gibbons and Dr. Lifton Q&A Transcript
May 29, 2013




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