A Step Closer to Resolving Birth Defects

Scientists have made a landmark discovery that could help women minimize or even avoid the risk of having a baby born with congenital birth defects. The study is published April 5 in the international journal Cell.

The scientists, from universities in Australia, Japan, Canada and the United States, including Arizona State University, show for the first time how “nature” and “nurture” interact to increase the severity and likelihood of developing birth defects, including abnormalities in the heart, kidneys, brain, limbs and cranio‐facial regions (cleft palate).

They show how hypoxia, or a period of low oxygen during pregnancy, combined with a genetic risk factor of having only one functioning copy of a gene, dramatically increases the chances of a baby being born with congenital scoliosis, a malformation of the spine that affects around 1 in 1,000.

Sally Dunwoodie, head of the Embryology Laboratory at the Victor Chang Cardiac Research Institute in Sydney, Australia, a professor at the University of New South Wales and the senior author on the study, says the findings take us a step closer to understanding why some people in families develop diseases and others don’t, and, importantly, simple strategies that mothers could adopt to help prevent such defects occurring.

“We’ve long suspected that it is genes or our environment that cause birth defects, but up until now, the majority of these have been largely unknown,” says Dunwoodie. “This is the first time anyone in the world has shown that both ‘nature’ and ‘nurture’, in combination, are molecularly responsible for causing many birth defects.”

“This research is hugely exciting and will help us to genetically diagnose a whole range of birth defects, and give advice to women on how and when to avoid certain activities when pregnant,” says Dunwoodie. “We hope it will eventually lead to the development of therapeutics to stop these defects occurring in the first place.”

Hypoxia during pregnancy can be caused by a range of circumstances including poorly controlled sugar levels in diabetics, smoking, high altitude, prescription and recreational drug‐use, anemia or a poorly functioning placenta.

“Just as genetic studies of selected families led to the discovery of genes causing breast cancer, this study of the genetics and development of congenital scoliosis will lead to breakthroughs in finding the factors that cause scoliosis, a disorder affecting up to 3 percent of the general population,” says co-author Kenro Kusumi, an associate professor in the School of Life Sciences in ASU’s College of Liberal Arts and Sciences.

One of the largest genetic studies focused on congenital scoliosis was led by Kusumi’s group. Together with clinical collaborators in Philadelphia and Toronto, the group identified the first case of a patient with congenital scoliosis due to having a single defective copy of the HES7 gene. Previous studies in mice had established that disruptions in this gene could lead to spinal defects, and loss of both copies of this gene had been found in severe cases of spinal deformities. The type of defect found in the patient in the ASU study was shown by Dunwoodie’s group to clearly affect the ability of the protein to function normally. This finding meant that having just one, instead of two functioning copies of a known gene from either mother or father, was a major risk factor for causing the abnormal formation of vertebrae in embryonic development.

Dunwoodie’s group then went on to test the genetic risk factor in a mouse model combined with an environmental insult in the form of hypoxia. Surprisingly, they found a marked increase in spinal abnormalities in the offspring, when the mothers were exposed to only 8 hours of low oxygen during an entire 21‐day pregnancy.

“We found that the combination of the genetic risk as well as exposure to low oxygen, resulted in our subjects being up to 10 times more likely to develop congenital scoliosis, than those that only had the genetic risk factor,” says Dunwoodie.

“What this brief period of low oxygen essentially did was disrupt the pathway responsible for development of the spine, and we know that the same pathway is used in the development of limbs and many organs, including the heart, kidneys, brain and cranio‐facial region,” adds Dunwoodie.

Bob Graham, a professor and executive director of the cardiac research institute, says around 25 percent of patients with congenital scoliosis also have some form of congenital heart defect, indicating that a single environmental ‘insult’ such as hypoxia, can potentially affect the development of more than one organ in the body.

“This study provides a new paradigm for the interaction between our genes and environment, and may account for a lot of diseases that we haven’t understood before, such as many different forms of congenital heart disease, and conditions like hair‐lip or cleft palate,” says Graham.

Kusumi points to a recent genetic study of over 50,000 identical twins that emphasizes that the risk of developing disease arises from the environment acting together with a person’s unique genome. “For scoliosis, our study highlights how environmental conditions, such as lack of oxygen reaching the developing embryo, could interact uniquely with each individual’s genetic differences to increase the risk of birth defects,” said Kenro.

“It may not necessarily be a lack of oxygen that allows the underlying gene defect to be revealed, it could be a lot of other environmental factors, such as anemia or lack of folate. But the message is, if you have family history of disease or you know you have a defective gene, mums need to be extra careful during pregnancy,” adds Graham.

The team of researchers has begun working on similar studies in congenital heart defects, which affect around 1 in every 100 babies born world-wide every year.