Using Systems Genetics to Probe for Gene Interactions in Congenital Heart Disease
Abstract
Congenital heart defects (CHDs) are the most common type of birth defects and affect about one percent of births per year. There are different types of heart defects, all of which interfere with the main function of the heart to efficiently pump blood through the body. Even minor defects that might go unnoticed for a long time often result in increased risk for arrhythmia or heart failure and death. Severe heart defects can often be surgically corrected right after birth but require lifelong monitoring that can add tremendous emotional and financial burden to the patient and family. The development of the heart is a complex interplay of many genes over time and space, and we know many key genes that are necessary for a heart to form properly. However, even in families with a history of congenital heart disease only about half of the cases can be explained by mutations in a single gene. This suggests that an unfavorable combination of several mutant genes is at the core of many CHDs, and it is their failed interactions that are driving the disease. The first step in identifying genetic defects is done using genome sequencing, and this technique is routinely and massively applied at hospitals throughout the country, delivering vast numbers of genetic variants but most often with little insight into a potential disease mechanism. We propose to establish a prototype for the analysis of genetic interactions during heart development and function. We will test thousands of genes in hearts of flies, by testing their interaction with two genes that are known to be extremely important for human heart development. These genetic interactions will provide a valuable blueprint for the classification of new disease candidate genes. In parallel, we will use a cell-based assay with material from CHD patients to directly test gene candidates in this human disease model with the aim to understand the effect of the specific genetic defects on cardiac development and function.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110104
Entities
People
- Georg Vogler
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army