Sequencing Shows Spontaneous Mutations Are Major Cause of Congenital Heart Disease

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 Dr. Richard Lifton. Dr. Lifton, who is at the 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 (NHLBI’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.
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