Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Spontaneous mutations are major cause of congenital heart disease

13.05.2013
Every year, thousands of babies are born with severely malformed hearts, disorders known collectively as congenital heart disease. Many of these defects can be repaired though surgery, but researchers don't understand what causes them or how to prevent them. New research shows that about 10 percent of these defects are caused by genetic mutations that are absent in the parents of affected children.

Although genetic factors contribute to congenital heart disease, many children born with heart defects have healthy parents and siblings, suggesting that new mutations that arise spontaneously—known as de novo mutations—might contribute to the disease.

"Until recently, we simply didn't have the technology to test for this possibility," says Howard Hughes Medical Institute (HHMI) investigator Richard Lifton. Lifton, who is at Yale School of Medicine, together with Christine Seidman, an HHMI investigator at Brigham and Women's Hospital and colleagues at Columbia, Mt. Sinai, and the University of Pennsylvania, collaborated to study congenital heart disease through the National Heart Lung and Blood Institute's Pediatric Cardiac Genomics Consortium.

Using robust sequencing technologies developed in recent years, the researchers compared the protein-coding regions of the genomes of children with and without congenital heart disease and their parents, and found that new mutations could explain about 10 percent of severe cases. The results demonstrated that mutations in several hundred different genes contribute to this trait in different patients, but were concentrated in a pathway that regulates key developmental genes. These genes affect the epigenome, a system of chemical tags that modifies gene expression. The findings were published online in the journal Nature on May 12, 2013.

For the current study, the investigators began with 362 families consisting of two healthy parents with no family history of heart problems and a child with severe congenital heart disease. By comparing genomes within families, they could pinpoint mutations that were present in each child's DNA, but not in his or her parents. The team also studied 264 healthy families to compare de novo mutations in the genomes of healthy children.

The team focused their gene-mutation search on the exome – the small fraction of each person's genome that encodes proteins, where disease-causing mutations are most likely to occur. Children with and without congenital heart disease had about the same number of de novo mutations -- on average, slightly less than one protein-altering mutation each. However, the locations of those mutations were markedly different in the two groups. "The mutations in patients with congenital heart disease were found much more frequently in genes that are highly expressed in the developing heart," Seidman says.

The differences became more dramatic when the researchers zeroed in on mutations most likely to impair protein function, such as those that would cause a protein to be cut short. Children with severe congenital heart disease were 7.5 times more likely than healthy children to have a damaging mutation in genes expressed in the developing heart.

The researchers found mutations in a variety of genes, but one cellular pathway was markedly enriched in the children with heart defects. That pathway helps regulate gene activity by affecting how DNA is packaged inside cells. The body's DNA is wrapped around proteins called histones, and chemical tags called methyl groups are added to histones to control which genes are turned on and off. In children with congenital heart disease, the team found an excess of mutations in genes that affect histone methylation at two sites that are known to regulate key developmental genes.

Overall, the researchers found that de novo mutations contribute to 10 percent of cases of severe congenital heart disease. Roughly a third of this contribution is from the histone-methylation pathway, Lifton says. He also notes that a mutation in just one copy of a gene in this pathway was enough to markedly increase the risk of a heart defect.

Direct sequencing of protein-coding regions of the human genomes to hunt down de novo mutations has only been applied to one other common congenital disease—autism. In that analysis, Lifton and his colleagues at Yale, as well as HHMI investigator Evan Eichler and colleagues at University of Washington, found mutations in some of the same genes mutated in congenital heart disease, and the same histone modification pathway appears to play a major role in autism as well, raising the possibility that this pathway may be perturbed in a variety of congenital disorders, Lifton says.

Even if the disease can't be prevented, identifying the mutations responsible for severe heart defects might help physicians better care for children with congenital heart disease. "After we repair the hearts of these children, some children do great and some do poorly," Seidman says. Researchers have long suspected that this might be due to differences in the underlying causes of the disease. Understanding those variations might help doctors improve outcomes for their patients.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Health and Medicine:

nachricht Speed data for the brain’s navigation system
06.12.2016 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)

nachricht Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Simple processing technique could cut cost of organic PV and wearable electronics

06.12.2016 | Materials Sciences

3-D printed kidney phantoms aid nuclear medicine dosing calibration

06.12.2016 | Medical Engineering

Robot on demand: Mobile machining of aircraft components with high precision

06.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>