Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.
Image credit: Darryl Leja, National Human Genome Research Institute, NIH, via Flickr, CC BY-NC 2.0 license.

In 1983, the median lifespan for people born with Down syndrome in the US was only 25 years. Today, due to better treatments for some of the most dangerous complications, that number has more than doubled. Despite these strides, many people with Down syndrome still die prematurely from congenital heart defects. In a recent study, Rambo-Martin et al. searched for clues about what causes some people with Down syndrome to be born with an atrioventricular septal defect (AVSD), one of these potentially deadly heart problems.

AVSD is present in one in five newborns with Down syndrome, making the defect 2000 times more common in individuals with Down syndrome than it is in the rest of the population. Down syndrome occurs when a person has an extra copy of part or all of chromosome 21, so the researchers hypothesized that mutations that disrupt genes on chromosome 21 could protect against Down syndrome-related AVSDs, since the dose of the disrupted gene would be reduced. They further hypothesized that the opposite would also be true: mutations that create extra copies of genes on chromosome 21 would further increase the dose of a duplicated gene, increasing the risk of AVSDs.

When they compared genetic data from people with Down syndrome with and without AVSDs, they found no specific gene on chromosome 21 that was most likely to be altered in those with the heart problem. This suggests that many interacting factors cause AVSDs in people with Down syndrome, which aligns with what we know about the causes of AVSDs in the rest of the population. Interestingly, this study attempted to replicate two significant findings on chromosome 21 from a previous study that had a smaller sample size. The prior study’s findings were not replicated in this cohort, which was four times larger, both when Rambo-Martin et al. used a similar technology and when they used a follow-up, gold-standard technology.

Despite the fact that this study is the largest of its kind so far, with over 400 participants, the authors say access to an even bigger sample could allow them to tease out smaller, but statistically significant, genetic relationships between Down syndrome and heart defects. Until a larger cohort becomes available, they suggest using exome and whole-genome sequencing to hunt for rare genetic variants that might predispose to the defects, as well as searching for potential environmental links.


Rambo-Martin, B.; Mulle, J.; Cutler, D.; Bean, L.; Rosser, T.; Dooley, K.; Cua, C.; Capone, G.; Maslen, C.; Reeves, R.; Sherman, S.; Zwick, M. Analysis of Copy Number Variants on Chromosome 21 in Down Syndrome-Associated Congenital Heart Defects.
G3, 8(1), 105-111.
DOI: 10.1534/g3.117.300366

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