CLUE TO GENETICS OF CONGENITAL HEART DEFECTS EMERGE FROM DOWN SYNDROME
Down syndrome is the most
common chromosomal abnormality in humans, involving a third copy of all or part
of chromosome 21. In addition to intellectual disability, individuals with Down
syndrome have a high risk of congenital heart defects. However, not all people
with Down syndrome have them -- about half have structurally normal hearts.
Researchers at Emory
University School of Medicine, with colleagues at Johns Hopkins University,
Oregon Health Science University, and University of Pittsburgh, report results
from the largest genetic study of congenital heart defects in individuals with
Down syndrome in the journal Genetics in Medicine.
The team found that
infants with congenital heart defects, in the context of Down syndrome, were
more likely to have rare, large genetic deletions. Those deletions tended to
involve genes that affect cilia, cellular structures that are important for
signaling and patterning in embryonic development.
These new findings,
along with other recent studies, suggest that the risk for congenital heart
defects in Down syndrome can come from several genes and environmental factors,
in addition to the substantial risk from the extra chromosome 21.
"In Down
syndrome, there's a 50-fold increase in risk for heart defects, which is
enormous," says senior author Michael Zwick, PhD, associate professor of
human genetics and pediatrics at Emory. "Studying congenital heart defects
in the 'at risk' Down syndrome population can make it possible to reveal genes
that impact the risk of heart defects in all children, including those with
typical number of chromosomes."
"Understanding
the origin of heart disorders in individuals with Down syndrome may reveal
aspects of biology that would allow better personalization of their health
care, since genetic alterations that affect the heart may also affect other
organs, such as the lungs or gut," Zwick says.
"Our partnership
with families who have a child with Down syndrome and our investment in a
comprehensive clinical data and biorepository will continue to provide
resources to study not only heart defects, but also other Down-syndrome associated
medical conditions such as cognitive function, leukemia, and dementia,"
says co-author Stephanie Sherman, PhD, professor of human genetics at Emory
University School of Medicine.
Sherman says the study
was a collaborative effort involving participants with Down syndrome, their
families and assessment sites across the United States, including those
mentioned above along with Kennedy Krieger Institute, Children's National
Medical Center and Ohio Nationwide Children's Hospital.
The first author was
Emory postdoctoral fellow Dhanya Ramachandran, PhD, working with Zwick. Emory
co-authors included assistant professors Lori Bean, PhD, Tracie Rosser, PhD and
David Cutler, PhD, in the Department of Human Genetics, and Jennifer Mulle,
PhD, assistant professor of epidemiology in the Rollins School of Public
Health. Ken Dooley, MD, associate professor of pediatrics at Emory and
pediatric cardiologist at Children's Healthcare of Atlanta, reviewed medical
records and made definitive diagnoses for all study participants.
The study included 452
individuals with Down syndrome. 210 had complete atrioventricular septal
defects (AVSDs), a serious heart defect that is relatively common among those
with Down syndrome (about 20 percent). The remaining 242 had structurally normal
hearts. The Emory team used high density microarrays to probe more than 900,000
sites across the human genome to detect structural variation, including
deletions or duplications of DNA.
An atrioventricular
septal defect means that the central region of the heart separating the atria
from the ventricles has failed to form properly. Such defects increase the
workload on the heart, and a complete AVSD leads to heart failure: fluid
buildup in the lungs and difficulty breathing, requiring surgery in the first
year of life.
The team's results add
to evidence for a connection between AVSDs and cilia. Ciliopathies are a class
of genetic disorders that include kidney, eye, and neurodevelopmental
disorders. Cells in the airways have mobile cilia which sweep mucus and dirt
out of the lungs, but almost every cell in the body has a primary (sensory)
cilium.
"The finding that
ciliome genes may be disrupted in children with Down syndrome and AVSD may
indicate differences in life-time care for these individuals," Zwick says.
"This is a suggestive result that needs replication in a larger
group."
To confirm and
strengthen the findings, Zwick and his team are currently performing an
independent study of individuals with Down syndrome, using whole genome
sequencing to further delineate alterations in genes that perturb heart
development in children.
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