The Genetics of Congenital Heart Defects Slowly Emerge from Down Syndrome Study
Down syndrome, of all the genetic defects people are born with, is the most common (as far as chromosomal abnormalities go). Down syndrome involves having a third copy of all or part of chromosome 21 (for those who do not recall we are typically born with 23 pairs of chromosomes). 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.
For this reason, geneticists have been learning about the causes of congenital heart defects by studying people with Down syndrome. The high risk for congenital heart defects in this group provides a tool to identify changes in genes — both on and off chromosome 21 — which are involved in abnormal heart development.
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.
“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.
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 team then 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 (for those who didn’t click the link) 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, it sounds like they would have nothing in common, however cilia are found on nearly every cell in the body. For example cells in the airways have mobile cilia which sweep mucus and dirt out of the lungs. As I mentioned before, almost every cell in the body has a primary (at least 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, the 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.
This could help benefit numerous people who suffer from genetic heart defects and also offer early screening techniques. With the advancement of gene therapy it is quite possible that one day we could simply remove or replace the genes involved, but that would be far, far into the future at this point in time.
Ramachandran D, Mulle JG, Locke AE, Bean LJ, Rosser TC, Bose P, Dooley KJ, Cua CL, Capone GT, Reeves RH, Maslen CL, Cutler DJ, Sherman SL, & Zwick ME (2014). Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genetics in medicine : official journal of the American College of Medical Genetics PMID: 25341113