New mutations that are absent in parents but appear in their offspring account for at least 10% of severe congenital heart disease, reveals a massive genomics study led, in part, by researchers at the Yale School of Medicine.
The analysis of all the genes of more than 1800 individuals found hundreds of mutations that can cause congenital heart disease, the most common form of birth defect that afflicts nearly 1% of all newborns. In particular, the study found frequent mutations in genes that modify histones, proteins that package DNA in the nucleus and orchestrate the timing and activation of genes crucial to development of the fetus. The results of the study, part of the Pediatric Cardiac Genomics Consortium funded by the NIH's National Heart, Lung, and Blood Institute (NHLBI), were published online May 12 in the journal Nature.
"These findings provide new insight into the causes of this common congenital disease," said Richard Lifton, Sterling Professor and chair of the Department of Genetics, investigator for the Howard Hughes Medical Institute, and a senior author of the paper. "Most interestingly, the set of genes mutated in congenital heart disease unexpectedly overlapped with genes and pathways mutated in autism. These findings suggest there may be common pathways that underlie a wide range of common congenital diseases."
"This is an important piece of the puzzle that gives us a clearer picture of the causes of congenital heart disease," said Gary H. Gibbons, M.D., director of the NHLBI. "What this international, multi-center collaborative research effort was able to accomplish, in a small amount of time, is truly remarkable. The state-of-the-art sequencing techniques that were used are allowing us to push the envelope and envision a day when we may be able to better treat and eventually prevent congenital heart disease in the early stages of heart formation."
The mutations can occur at the same site, and both increase and decrease the modification histone proteins, said Martina Brueckner, professor of pediatrics and genetics at Yale and another senior author of the study. The results suggest a very sensitive developmental system that might also be influenced by environmental factors in development.
"These findings point to fundamental mechanisms that play a role in a wide range of congenital diseases," Lifton said.
Samir Zaidi and Murim Choi of Yale were co-lead authors of the paper. Researchers from Harvard University, Columbia University Medical Center, the Perelman School of Medicine at University of Pennsylvania, and Icahn School of Medicine at Mt. Sinai shared senior authorship.