Three genes form the ‘recipe’ for children born with severe heart defects, scientists discover 

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

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

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

By studying the genomes of a family with several children that suffer the disease, Gladstone Institutes have discovered three gene mutations they believe causes congenital heart disease. 

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

‘The idea that several genetic variants are necessary to cause most complex diseases has been around for a long time, but proving it has been difficult,’ said Dr Casey Gifford, first author of the paper and a Gladstone scientist. 

‘With the advent of CRISPR genome editing 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.’ 

Studying families with a history of disease helps scientists identify what it is about them – whether their DNA or their environments – that might make them different and more at-risk than other people. 

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

Because the broad array of structural issues form in the womb, their origin is hard to parse out. 

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

But it’s never been enough to explain the full scope of or worst cases of the defects. 

And without knowing their causes, there has been little to do to prevent congenital heart defects. 

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

The family’s two-month had gone into heart failure once already because their left ventricle’s under-developed cells couldn’t contract properly, their four-year old had a similar condition and what would have been a third sibling died during the third trimester of the mother’s pregnancy. 

It later came out that the father, too, had a milder, adult version of the disease. 

‘Given the severity of the disease in the children and the fact that one of the parents had an asymptomatic form, we suspected that the condition in the children was caused by a combination of the mother and the father’s genes,’ said study co-author, Dr Deepak Srivastava, the University of California, San Francisco cardiologist that identified the family. 

The researchers sequenced the entire family’s genome. 

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

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

The children inherited all three mutations, so the researchers couldn’t be automatically sure if it was one, two or all three genes causing the heart defects. 

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

Inheriting any one gene did nothing abnormal to the mice’s hearts, but animals with alterations to all three genes had almost identical forms of heart disease to the human children from the family. 

And the researchers saw that these thee combined genetic changes had cascading effects on other bits of DNA that encode the way that the heart and blood vessels develop. 

They even coaxed stem cells from the children and each parent into developing into beating heart cells. The parents were normal, while the childrens’ were diseased, further confirming that it was the combination of the three mutations that caused disease.  

‘This work finally provides experimental proof of how a modifier gene might be functioning to influence the disease process in humans, and how multiple genes work together to cause human disease,’ said Dr Srivastava. 

‘It points us to a way that you could make a mutation in a gene better or worse depending on what it’s combined with. This discovery opens the door to identifying genetic modifiers of disease and using them as targets to develop novel therapeutics.’ 

When the compared their data to previous research, they saw that one gene was present in people with many forms of heart defects, while another was far less common in people with disease,suggesting that MYH7 may control the risks of heart defects, but MYH7 determines the specifics. 

It’s not yet clear how many people with heart defects have each of these genes, but nonetheless may open a doorway to a path to treatment or prevention.