Genetic Mutation Linked Congenital Heart Defect
July 30, 2013

Rare Genetic Mutation Linked To Congenital Heart Defects

April Flowers for - Your Universe Online

A team of scientists from The Research Institute at Nationwide Children'sHospital has found a mutation in a gene crucial to normal heart development could play a role in some types of congenital heart defects - the most common birth defect in the US. The findings were published in the journal Human Mutation and could help narrow the search for genes that contribute to this genetic defect, which affects as many as 40,000 newborns a year.

So far, several hundred genes have been implicated in the formation of the heart. Mutation in any one of those genes could potentially contribute to a cardiac defect. Vidu Garg, MD, is the principal investigator in the Center for Cardiovascular and Pulmonary Research and director of Translational Research in The Heart Center at Nationwide Children's. He says identifying which of these genes is responsible for human congenital heart disease has been a challenge for researchers.

"We have to ask ourselves, what subset of the more than 20,000 genes that make up the human genome are contributing to congenital heart disease?" he says. "Right now, we don't know enough about a lot of those genes, so this study provides another piece of the puzzle."

That puzzle piece is the so-called FOXP1 gene, a member of a large gene family that helps regulate tissues throughout the body, including in the heart, lungs and brain. Previous studies of FOXP1 have described its function and role in the development of the heart in animal models, but it took a former colleague calling up Dr. Garg to report the results of particularly interesting case to make him take a closer look at the gene.

Linda Baker, MD, from the University of Texas Southwestern Medical Center, found a rare genetic abnormality while analyzing a DNA sample from an 8-month-old infant who died from complications of complex congenital heart disease. The abnormality was a small chromosomal deletion in the FOXP1 gene.

Dr. Garg's team performed a search of DNA samples from patients with congenital heart disease in a repository at Nationwide Children's - one of the largest in the nation - which revealed two additional patients with a similar heart defect who also had a rare mutation in the same gene.

The team analyzed the gene and found this mutation affected the gene's ability to express a transcription factor called Nkx2.5, which has been implicated in congenital heart disease.

"If you have three unrelated people with an abnormality in the same gene, and they also have an extremely rare type of congenital heart disease, there's a high likelihood that the gene is contributing to the condition," says Dr. Garg, who also is an associate professor of pediatrics at The Ohio State University College of Medicine. "Understanding how either deletion or loss of FOXP1 affects normal heart development could help contribute to our understanding of congenital heart disease."

The team plans further research to see if they can find the FOXP1 mutation in patients with different types of congenital heart disease. Then, they plan to look at how the gene interacts with others involved in the formation of a normal heart. Dr. Garg says that it is possible, given congenital heart disease is probably the result of mutations in many genes, that by studying this gene and its potential partners, we can uncover other potential candidate genes for heart malformations.