Congenital heart disease is a leading cause of death in children, exacting a substantial emotional and economic toll. To study the mechanisms of congenital heart disease, most research has sought to identify genetic mutations in human patients or to dissect cardiac developmental pathways in animal models, but the knowledge garnered has not suggested clear strategies for treatment or prevention. On the other hand, individuals who have the same mutation commonly have presentations ranging from normal to life-threatening. Such "experiments of nature" suggest that unknown factors modify the phenotypic expression of a mutation. If these factors were understood, they might be therapeutically mimicked to prevent or ameliorate disease in others. Our long term goal hence is to dissect the basis of incomplete penetrance and phenotypic pleiotropy. Mutation of the cardiac transcription factor NKX2-5 was one of the first among more than a dozen genes known to cause human congenital heart disease. NKX2-5 mutant phenotypes include normal hearts, simple atrial and ventricular septal defects (ASD, VSD), and complex malformations like double outlet right ventricle. To characterize the sources of phenotypic variability, we crossed inbred mouse strains to show how genetic and non-genetic factors affect the development of heart defects. Preliminary linkage analyses in the F2 intercrosses have identified multiple modifier loci for individual defects and led to a candidate VSD modifier gene. In addition, one cross replicates the commonly reported human epidemiologic association of older maternal age with an increased risk of congenital heart defects independent of any chromosomal abnormality. The maternal age effect strongly interacts with a modifier locus on chromosome 10. Thus, our guiding hypothesis is that modifier genes buffer cardiac developmental pathways against genetic and environmental insults in the majority of a population while directing the manifestation of disease in a few. Characterization of the genetic architecture of congenital heart disease in a mouse model will lead to a deeper understanding of its multifactorial basis and possibly novel strategies for prognosis and prevention.

Public Health Relevance

Congenital heart disease is a leading cause of death in children, incurring enormous emotional and economic costs on our nation. Our research seeks to understand the factors that affect whether individuals who share a common cause develop a heart defect and the particular type. Understanding how some individuals who have no or only mild disease could suggest ways to prevent heart defects in others.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105857-04
Application #
8588986
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Schramm, Charlene A
Project Start
2010-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$342,000
Indirect Cost
$117,000
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Prendiville, Terence; Jay, Patrick Y; Pu, William T (2014) Insights into the genetic structure of congenital heart disease from human and murine studies on monogenic disorders. Cold Spring Harb Perspect Med 4:
Gazit, Avihu Z; Li, Alex; Choi, Jacob S et al. (2014) Ex vivo, microelectrode analysis of conduction through the AV node of wild-type and Nkx2-5 mutant mouse hearts as guided by a Cx40-eGFP transgenic reporter. Physiol Rep 2:e00285
Nguyen, Hoang H; Jay, Patrick Y (2014) A single misstep in cardiac development explains the co-occurrence of tetralogy of fallot and complete atrioventricular septal defect in Down syndrome. J Pediatr 165:194-6
Chen, Iuan-bor D; Rathi, Vinay K; DeAndrade, Diana S et al. (2013) Association of genes with physiological functions by comparative analysis of pooled expression microarray data. Physiol Genomics 45:69-78
Winston, Julia B; Schulkey, Claire E; Chen, Iuan-Bor D et al. (2012) Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation. Circ Cardiovasc Genet 5:293-300