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[Kaltman] Hi, my name is Jon Kaltman.
I’m from the Division of Cardiovascular Sciences
at the National Heart, Lung, and Blood Institute.
And I’m here with Dr. Rick Lifton,
the head of the Department of Genetics from Yale University.
Thank you for being with us.
[Lifton] My pleasure. Thanks.
[Kaltman] So what were the important findings
from the NHLBI-supported Pediatric Congenital Heart Genomics Consortium’s
main paper that’s going to be published in Nature?
[Lifton] So as you know, congenital heart disease is the most common birth defect,
affecting up to 1 percent of all live births.
And its cause has been almost entirely unknown.
So this paper for the first time demonstrates
a role of mutations in particular genes
that contribute to the pathogenesis of about 10 percent of these cases.
And this is a major step forward in this disease.
[Kaltman] What makes this research unique, or this particular research project?
[Lifton] So this is the first large-scale study of mutations of this type
in congenital heart disease.
And really provides a first look at whether these kinds of mutations account for
the frequent pattern in families where you’ll have healthy parents
who quite unexpectedly have a child with a severe congenital heart disease.
And these studies for the first time provide insight that
these kinds of mutations can play a very significant role
in the causation of a significant fraction of these patients.
[Kaltman] Why is it important to study the genetic causes of congenital heart disease?
[Lifton] Well so there are many reasons.
Obviously one of the hopes will be in the long run
if we understand the pathogenesis well enough
we might be able to prevent its causation.
A second opportunity is we know in the clinic that
when we see patients with severe congenital heart disease that
despite having apparently the same structural heart disease,
after repair they may have very different clinical outcomes.
And right now we’re pretty well flying blind in trying to understand
who is going to do well and who is not.
And the opportunity to identify specific patients who
have the same structural heart disease due to different causes
may allow us to recognize what are the factors that are determining this.
And this can be very important in enabling us to intervene early
in children who are destined to have poorer outcomes.
[Kaltman] How do you think the findings from this research project
will inform future research in the causes of congenital heart disease?
[Lifton] So I think one of the really striking findings from this study was
not just the finding that there are in general more de novo mutations
but there’s a particular pathway that is frequently mutated in these patients.
And that’s a pathway that we’ve known for a number of years
regulates how genes are expressed by changing subtle aspects of chromatin
(the way DNA is packaged with protein into chromosomes)
and many of the mutations that we find affect this pathway
of chromatin modification. And this drastically changes
the way we will be thinking about this disease going forward.
For example we now recognize this pathway
and can simply go in and start sequencing additional patients
looking for mutations in genes in this pathway,
and I think that part of the story is particularly compelling because
it’s a very nice tie from what’s been recognized
in gene expression and developmental biology and takes it for the first time
to human biology and in particular congenital heart disease.
And this I think will shape research for years to come.
[Kaltman] So Dr. Lifton, thank you so much for your efforts
on behalf of the Pediatric Cardiac Genomics Consortium
and thank you for coming today to describe this very interesting work.
[Lifton] My pleasure. Thanks for the opportunity.