Discovery Files

Study shows loss of gene function is causal to congenital heart disease

Congenital heart disease is the most common type of birth defect

A team of researchers co-led by Michael Frohman of Stony Brook University has identified an important cause of congenital heart disease. The researchers discovered that certain loss of functions in the PLD1 (phospholipase D1) gene causes congenital right-sided cardiac valve defects and neonatal cardiomyopathy. The findings are detailed in a paper in the Journal of Clinical Investigation. The research was funded in part by the U.S. National Science Foundation.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies, with a worldwide occurrence of seven per thousand births. The majority of these defects include abnormalities of valve formation.

Congenital heart disease caused by loss of PLD1 function generally leads to mis-development of the cardiac valves on the right side of the heart and sometimes the right ventricle. This improper development of the heart sometimes prevents live birth, and in most other cases thus far, the newborns would not survive without surgery or drug management.

The team used whole-exome sequencing and other approaches in 2,718 congenital heart disease cases to identify 30 patients from 21 unrelated families of different ancestries with altered PLD1 genes on both chromosomes who presented with congenital cardiac valve defects. The investigation also demonstrated that PLD1 inhibition decreases endothelial mesenchymal transition, an early step in embryonic development of the valves at around the seventh week of pregnancy.

One of the mutations in PLD1 is at a high enough rate, 2%, in Ashkenazi Jews that the mutation may be incorporated into prenatal genetic testing.