Approximately one in every 100 babies is born with congenital heart disease (CHD), and CHD remains the leading cause of mortality from birth defects. Although advancements in surgery and care have improved rates of survival for these infants, CHD patients remain at elevated risk for heart complications later in life, other congenital abnormalities and neurodevelopmental deficits. With relatively little known about the genes underlying many cases of CHD, pressing questions from parents about their children’s future health and about risk of CHD for future offspring remain difficult for physicians to answer. But a new study from the NHLBI Pediatric Cardiac Genomics Consortium (PGCG), part of the Bench to Bassinet Program, has helped shed new light on some of the underlying genetic causes of cases of CHD as well as the long-term outlook for patients who carry these mutations. The team, led by researchers at Brigham and Women’s Hospital, publishes its latest findings in Nature Genetics this week.
“As a clinician, there’s nothing more devastating than when parents ask us about future risk for a child with CHD or for having another child, and we have to tell them, ‘We don’t know,’” said co-corresponding author Christine Seidman, MD, director of the BWH Cardiovascular Genetics Center and Howard Hughes Medical Institute investigator. “The discoveries revealed through this work not only teach us about the fundamental biology through which the heart gets built, but also have important clinical implications: Detecting these mutations could help us alert patients and parents to risk of ongoing problems that can be addressed and managed, and define risk for a second child.”
The new study, conducted in collaboration with researchers at seven academic centers across the U.S., leverages clinical and genetic data from more than 2,800 patients with CHD as well as information from parents. This allowed the researchers to determine which genetic mutations had been passed from parents to offspring and which had appeared spontaneously in the child’s genome (known as de novo mutations). The team reports several important findings:
These new findings could be used to expand current genetic testing panels for CHD, to improve both information for parents about the recurrence risks in future children, and the long-term care of the CHD infants. Seidman notes that while this research is still ongoing, these findings already indicate that as many as 400 genes contribute to CHD. Given that, sequencing a baby’s whole genome may be a better approach than screening for specific mutations.
“Whole-genome sequencing may be the most effective way to detect genetic variants that cause birth defects and may effect a child’s short- and long-term care,” said Seidman.
This work was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences (U01 HL098153 and UL1TR000003), National Institutes of Health, grants to the Pediatric Cardiac Genomics Consortium (U01-HL098188, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123 and U01-HL098162), the NIH Centers for Mendelian Genomics (5U54HG006504), the Howard Hughes Medical Institute, the Simons Foundation (WKC), the James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowship at the Yale University School of Medicine, the John S. LaDue Fellowship at Harvard Medical School, the Alan Lerner Research Award at the Brigham and Women’s Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Heart, Lung, and Blood Institute, the National Center for Research Resources or the NIH.