Clues to genetics of heart defects in Downs
The risk of atrioventricular septal defect — AVSD— is higher in children with Down syndrome. In AVSD, the central region of the heart fails to separate the atria from the ventricles.
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. But, not all people with Down syndrome are afflicted – about half have structurally normal hearts.
The high risk for congenital heart defects with Downs helps to identify changes in genes, both on and off chromosome 21.
Researchers at Emory University School of Medicine, and colleagues at Johns Hopkins University, Oregon Health Science University, and University of Pittsburgh, published their results — from this largest genetic study of congenital heart defects in Down syndrome — in the journal Genetics in Medicine.
Researchers found Down syndrome infants with congenital heart defects were more likely to have rare, large gene deletions. These deletions tend to affect cilia — cell structures important for signaling and patterning in embryo development. Cilia are the slender protuberances projecting from the cell body.
These new findings along with other recent studies, suggest the risk for congenital heart defects in Downs can come from several genes and environmental factors outside the substantial risk from an extra chromosome 21.
“Understanding the origin of heart disorders in individuals with Downs may reveal aspects of biology that would allow better personalized health care, as genetic alterations that affect the heart may also affect other organs such as the lungs or gut."
Michael Zwick PhD, enior author and associate professor, human genetics and pediatrics, Emory University.
The study included 452 individuals with Down syndrome. Of those participants, 210 had complete atrioventricular septal defects (AVSDs), a serious heart defect relatively common (about 20 percent) among Downs. The remaining 242 had structurally normal hearts. The Emory team used high density microarrays to probe more than 900,000 sites across these individuals' genomes to detect structural variation, including deletions or duplications of DNA.
An atrioventricular septal defect means the central region of the heart separating the atria from the ventricles has failed to form correctly. The defect increases the workload on the heart. Complete AVSD leads to heart failure from fluid buildup in the lungs and difficulty breathing, requiring surgery in the first year of life.
Research results give evidence connecting AVSDs with cilia errors. Ciliopathic gene errors can include kidney, eye, and neurodevelopmental disorders.
To confirm and strengthen their findings, Zwick and team are currently performing independent study of individuals with Down syndrome, using whole genome sequencing to further delineate altered genes that perturb heart development in children.
The goal of this study was to identify the contribution of large copy-number variants to Down syndrome–associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population.
Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background.
Large, common copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome–associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P < 0.01) and intersected more genes (P < 0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls.
Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome–associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome–associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.
Genet Med advance online publication 23 October 2014
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 research was supported by the National Heart Lung & Blood Institute (HL092981, HL083300) and the National Institute of Child Health and Human Development (HD38979).
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