Genetic causes of congenital heart disease identified, researchers reveal


Congenital heart disease (CHD) is the leading cause of mortality from congenital disabilities affecting about one in every 100 babies. CHD patients remain at a higher risk of heart complications later in life, despite an increase in survival rates of infants due to advancements in surgery and care. The genetic cause underlying CHD is undefined, while a new study from the NHLBI Pediatric Cardiac Genomics Consortium (PGCG) uncovered the genetic causes of cases of CHD and the long-term effects for patients with these mutations.

The researchers from Brigham and Women's Hospital published their study findings in Nature Genetics.

Christine Seidman, director of the BWH Cardiovascular Genetics Center, said, "As a clinician, there's nothing more devastating than when parents question about future risk for a child with CHD or for having another child, and we have to tell them, 'We don't know.'" The fundamental biology of heart physiology is clear, but its clinical implications, detecting mutations which can aid in addressing and managing the ongoing problems as well as risks for the second child need to be defined.

Over 2,800 patients with CHD were analyzed for clinical and genetic data including information from parents. In association with researchers at seven academic centers across the U.S., the researchers identified which genetic mutations were passed from parents to offspring and which had appeared spontaneously in the child's genome (de novo mutations).

Certain genetic mutations which transmitted from parents to children included:

  • Mutations in FLT4 gene caused Tetralogy of Fallot or "blue baby syndrome."
  • Mutations in gene encoding myosin accounted for 11% of Shone syndrome.
  • Identical mutations in both gene copies of GDF1 accounted for about 5% of severe CHD among children of Ashkenazian descent and could have clinical implications for evaluating risk among individuals with this ancestry.

Certain genetic mutations are seen in child’s genome for the first time:

  • The de novo mutations were reported in several genes, in particular, that modify chromatin.
  • These mutations are observed in CHD children with neurodevelopmental issues and other congenital defects. Previously, these same genes were associated with autism which in turn results in high rates of neurocognitive problems in some CHD cases.

Current outcomes may be used to expand current genetic testing panels for CHD. The risk of recurrence in future children, as well as long-term care of the CHD infants, could be addressed.  While Seidman notes that the research is ongoing, about 400 genes were known to contribute to CHD.

Seidman concludes, "Whole-genome sequencing may be the most effective way to detect genetic variants that cause congenital effects and may affect a child's short- and long-term care."