Three genes form the recipe & # 039; for children born with serious heart defects, scientists discover

Three gene mutations are a recipe for a disastrous, deadly congenital heart disease, a new study has found.


About one percent of all children born with congenital heart disease, a condition that causes lifelong – and sometimes fatal – heart disease.

Scientists have long suspected that this form of heart disease is at least partially genetic, but the exact cause and DNA have remained unclear so far.

By studying the genome of a family with multiple children suffering from the disease, Gladstone Institutes have discovered three gene mutations that they think cause congenital heart disease.

More than 1.3 million people in the US were born with congenital heart disease - and now scientists have discovered how three genes work together to cause the condition (file)

More than 1.3 million people in the US were born with congenital heart disease – and now scientists have discovered how three genes work together to cause the condition (file)

& # 39; The idea that different genetic variants are needed to cause the most complex diseases has been around for a long time, but proves that it was difficult & # 39 ;, said Dr. Casey Gifford, lead author of the article and a Gladstone scientist .


& # 39; With the advent of CRISPR genome processing and improvements in human pluripotent stem cell technology, we felt that we finally had the right tools to test this hypothesis once we found the right case to study. & # 39;

By studying families with a history of diseases, scientists can determine what they are up to – their DNA or their environment – making them different and more at risk than other people.

More than 1.3 million people in the US have congenital heart disease and around 40,000 children are born with a form of the condition each year.

Because the wide range of structural problems arise in the womb, their origins are difficult to dissect.

Some cases can be traced to infections during pregnancy, other rare cases to mutations of a single gene.

But it has never been enough to explain the full extent or worst cases of the defects.

And without knowing the causes, there was little to do to prevent congenital heart defects.


Until the Gladstone researchers found a family in which two children had serious heart defects, and a third died as a fetus in the mother's womb.

The two-month family had already suffered heart failure because the cells of their left ventricle could not contract properly, their four-year-old had a similar condition, and what a third brother or sister would have died during the third trimester of pregnancy. mother's pregnancy.

It later turned out that the father also had a milder, adult version of the disease.

& # 39; Given the severity of the disease in the children and the fact that one of the parents was asymptomatic, we suspected that the disease in the children was caused by a combination of the mother and the father's genes, & # 39; said co-author, Dr. Deepak Srivastava, the University of California, cardiologist in San Francisco who has identified the family.

The researchers have sequenced the genome of the entire family.


The father had two mutated genes – MKL2 sand MYH7, which are associated with heart disease, but only change one amino acid.

Although the mother's heart was normal, the genome sequencing revealed that she also had a mutation on the NKX2-5 gene, another that changes a single amino acid.

The children inherited all three mutations, so the researchers could not automatically be sure whether it was one, two or all three genes that caused the heart defects.

So they used the CRISPR gene editing tool to experiment with different variations and combinations of the genes in mice.

Adopting one gene did not make the mice's hearts anything abnormal, but animals with changes to all three genes had almost identical forms of heart disease for the human children in the family.


And the researchers saw that these combined genetic changes had cascade effects on other pieces of DNA that encode the development of the heart and blood vessels.

They even persuaded the children's and every parent's stem cells to develop into beating heart cells. The parents were normal while the children were sick and further confirmed that it was the combination of the three mutations that caused disease.

& # 39; This work ultimately provides experimental evidence of how a modifying gene might function to affect the disease process in humans, and how multiple genes work together to cause a human disease & # 39 ;, said Dr. Srivastava.

& # 39; It points us to a way in which you can make a mutation in a gene better or worse, depending on where it is combined. This discovery opens the door to the identification of genetic modifiers of diseases and their use as a target to develop new therapeutics. & # 39;

When they compared their data with earlier research, they saw that one gene was present in people with many forms of heart disease, while another gene was much less common in people with disease, suggesting that MYH7 reduced the risk of heart disease. can control, but MYH7 determines the details.


It is not yet clear how many people with heart disease have each of these genes, but nevertheless open a door to a path to treatment or prevention.

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