Nearly 1 in every 100 babies is born with a heart defect. These are the most common type of birth defect and can range from simple, symptomless cases to life-threatening conditions that require treatment within hours of birth.
Environmental influences such as excessive alcohol consumption or exposure to other toxins are known to cause heart defects. But many are also the result of faulty genes that can be passed on from one generation to the next. Identifying the genes involved is key to understanding when a baby might be at risk, and could also help us develop new ways to treat or prevent these heart defects. But with more than 20,000 genes in the human genome there are a mind-boggling number of possibilities.
A screen of mouse embryos by the DMDD programme (Deciphering the Mechanisms of Developmental Disorders) has identified a huge number of genes related to heart defects and other developmental abnormalities, and is now a potential goldmine of information on the genetic basis of heart conditions. Part of an open data initiative by the Wellcome Trust, the project has made all of its data available online, with a goal to spark further research into heart defects and rare disease.
INACTIVATING GENES TO UNDERSTAND RARE DISEASE
The DMDD team studies mouse embryos that have been bred to have a single one of their 20,000 genes inactivated – a process that’s known as knocking out a gene. As each embryo grows, any abnormalities in the way it develops are likely to be due to the missing gene and this provides powerful information about the sort of birth defects that the gene could be linked to. Although we might look very different, mice and humans are thought to share around 98% of our genes, so the effects of a missing gene on a developing mouse can tell us a lot about what we might expect if the same faulty gene is found in humans.
We concentrate specifically on genes that when knocked out cause a mouse embryo to die before birth. On the face of it, studying these genes might not seem so important to people living with rare genetic diseases – these people have already survived past birth. But genes like these are a rich source of information about human genetic diseases.
Many rare disease patients have mutations that act as genetic dimmer switches, increasing or decreasing a gene’s activity rather than completely turning it off. A particular gene may only be partially turned on (called a hypomorph mutation) or it may be turned on more than normal (known as a hypermorph mutation). If we are able to understand the effect of fully turning off a gene, we can then begin to infer what might happen to patients who have a hypomorph or hypermorph mutation.
By the end of the project, DMDD will have studied the effects of 250 different gene knockouts – it’s a huge opportunity to learn more about genetic causes of rare diseases in humans. And the biggest surprise in the results so far is the overwhelming prevalence of defects in the developing embryo hearts.
IDENTIFYING HEART DEFECTS
So far the team have analysed more than 200 embryos, each with one of 42 different genes knocked out. But unexpectedly, more than 80% of the gene deletions resulted in heart defects. Using an imaging technique called High Resolution Episcopic Microscopy the embryos were reconstructed in incredible 3D detail and studied down to the level of individual nerves and blood vessels. In the image below, the developing embryo heart is less than 2 mm across – smaller than the thickness of a matchstick – yet even the tiniest abnormality can be picked up.
“Even though we know that heart defects are common, we were really surprised that they were caused by more than 80% of our gene deletions. The data is a potential goldmine of information about the genetic basis of many different types of heart condition.” Dr Tim Mohun, DMDD.
The most common defects were problems with the walls that separate the right and left chambers of the heart. But there were also many defects in the heart valves, the outflow vessels (which carry blood out of the heart to the body or the lungs) and in the structure of the heart itself.
Several of the gene knockouts result in developmental defects that mimic known human genetic disorders. For example knocking out the genes Psph or Psat1 causes a range of developmental defects that appear similar to Neu-Laxova syndrome, a serious condition that leads to miscarriage or neonatal death. Tim Mohun commented “we know that many rare genetic diseases cause problems with the heart as it develops. Having so much new data about heart defects is exciting, because there is the potential for us to learn more about rare disease.”
THE PLACENTA: A NEW WAY TO UNDERSTAND THE HEART?
In the first study of its kind the placentas from a large collection of knockout embryos have also been analysed, and the results show an unexpected link between the placenta and the heart. Around a third of gene knockouts that cause placental abnormalities also cause a heart defect in the developing embryo. A more detailed statistical study of the data (publication in progress) has shown that this is a genuine link. Myriam Hemberger of the Babraham Institute, who performed the work as part of the DMDD programme, said “it could be that the restricted nutrient supply or blood circulation defects caused by an abnormal placenta adversely affect heart development. It does suggest there is more we could learn about some rare heart conditions by studying the placenta.
[The results] suggest there is more we could learn about some rare heart conditions by studying the placenta. Myriam Hemberger, DMDD.
Initial analysis of the DMDD embryo and placenta data has shown it to be a rich resource for those studying rare disease and developmental disorders. But, unexpectedly, it may shed particular light onto the genetic basis of heart disease.