A single ventricle (SV) heart defect occurs when there is an abnormal development in the fetal heart during early pregnancy. The origins of these abnormalities are unknown, but genetic factors play an important role and may provide insights into heart development and disease. 

“We don't know how to find those changes or recognize the changes that lead to single ventricle defects,” says Jesse Engreitz, PhD, Assistant Professor in the Department of Genetics at Stanford School of Medicine. “What we'd like to do is sequence the genome of a patient that has a single ventricle disease, find the genetic changes that caused the disease, and then use those genetic changes to learn about the cellular processes that control the formation of the heart.”

Dr. Engreitz is currently leading a project to understand the genetic underpinnings that lead to SV diseases. Specifically, the project is to create a map of the genome in heart development as a foundation for identifying the genetic changes that influence SV malformations. He received total funding of $142,000 in 2020 through MCHRI’s Additional Ventures Innovation Fund Single Ventricle Disease Research Awards Program to conduct this research.

This project involves the collective expertise of Sean Wu, MD, PhD, Associate Professor of Cardiovascular Medicine, William Goodyear, MD, PhD, Instructor in Pediatric Cardiology, Sharon Paige, MD, PhD, and James Priest, MD.

Understanding the sequence of events 

Genetic variation plays a vital role in the makeup of SV heart defects. Dr. Engreitz and his team want to identify which of the thousands of genetic variants influence the cells and genes critical for heart development. 

One way these diseases occur, says Dr. Engreitz, is when a change occurs in our genome that affects the function of genes that control heart development. If we could understand the sequence of events from the variant to the cell type to the gene, we could learn why these diseases occur and identify ways to prevent or treat them.

“What we're trying to do in this project is identify all of those regulators; in particular, identify dials [or enhancers] in genes with particular roles that turn on and off during heart development,” explains Dr. Engreitz. Cataloging these enhancers in fetal human heart development will help the team better understand which cell types are responsible for controlling heart development.

Furthermore, building a comprehensive map of all of these dials in the fetal heart will complement existing databases of genetic variation. The regulatory mapping will provide a foundational resource for understanding how genetic variation affects heart development and identify genes and cell types responsible for the etiology of SV heart disease.

“Ultimately, we will then use those dials to interpret genetic variants that are associated with single ventricle diseases,” says Dr. Engreitz.

Current progress and long-term goals

In the last six months, Dr. Engreitz and his team have optimized experimental techniques and made arrangements with the Stanford Division of Family Planning Services and Research to collect fetal heart tissue. Once they collect the sample, they will analyze the regulatory programs of the fetal heart tissue through a technology called single-cell chromatin accessibility sequencing, which examines the individual cells' genetic information.

The team will then build maps by applying computational algorithms to determine which dials control which genes and intersect these maps with the genetic variants that occur in patients with SV defects.

The long-term goal for the project is to develop a comprehensive regulatory map of heart development, allowing scientists to understand the cellular processes in the formation of an SV defect and how these genetic variants disrupt heart development. This includes having complete information on underlying genetic defects and creating new options for surgical interventions or tissue regeneration.

“That might have implications for how we treat and improve the lives of patients,” says Dr. Engreitz.                                              

The project is currently in progress. This story is a complimentary piece to a larger article. To read the article, click here.

BY ROXANNA VAN NORMAN

Roxanna Van Norman is the marketing manager for the Stanford Maternal and Child Health Research Institute.