Extraordinary technologic advances over the past two decades have provided unparalleled opportunities to sequence DNA, identify pathogenic mutations and recapitulate disease in model organisms and human cells. These innovations have fueled the discovery of genetic causes and mechanisms for human heart disease.
“These discoveries are setting the stage for new opportunities to target individuals who are at risk for disease with interventions that may delay or prevent clinical expression,” said Christine Seidman, MD, the Thomas W. Smith Professor of Medicine at Harvard Medical School, and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital in Boston.
Seidman delivered the Distinguished Scientist Lecture on Tuesday. She discussed the evolution of cardiovascular genetics in the context of congenital heart disease, citing pediatric cardiology pioneer Helen Taussig, MD, one of the first scientists to recognize that the likelihood of genetic etiologies for congenital malformations was considerable.
“She recognized that neither exposure to toxic substances nor the health of the parents of young children were suitable to define the abnormalities that sometimes arise,” Seidman said. “Despite her enormous insights into this likely etiology, her ability to tackle the problem was really quite limited. But after her death, the role of identifying familial causes of congenital heart disease began and has really flourished now for several decades.”
Scientists soon recognized, Seidman said, that families in which these mutations are inherited are very rare. Because the defects are inherited, the malformations are generally mild and typically only involve minor septation defects.
“Despite these rarities, they were very informative mutations because all of them resulted in a loss of function of the encoded protein and turned out to interrupt the function of a class of molecules — cardiac conscription factors,” Seidman said.
Unfortunately, this insight is not applicable to much more severe forms of congenital heart disease, such as tetralogy of Fallot, transposition of the great arteries and hypoplastic left heart syndrome.
The National Heart, Lung, and Blood Institute funded the creation of the Pediatric Cardiac Genetics Consortium in 2009. It comprises some of the leading cardiovascular research labs in the U.S. to address the potential genetic etiologies of more severe cardiac malformations, Seidman said.
“What we have postulated over the past five years is that de novo mutations arise in the embryonic egg or sperm, ultimately resulting in a child with critical congenital heart disease that obviously was absent from either of the parental genomes,” Seidman said. “What we were looking for in our sequence analyses was a Mendelian error, if you will.”
Ongoing research has led to the identification of specific mutations that perturb genes involved in anatomic structure, morphogenesis and developmental processes. The details will be published in the journal Science later this year.
“What we’re learning is enormously informative of a new genetic cause of congenital heart malformation and is going provide a wide range of opportunities to discover the developmental signals that are critical for shaping the normal human heart,” Seidman said.